Journal articles on the topic 'Receptors, Death Domain'
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1
Wajant, Harald. "Death receptors." Essays in Biochemistry 39 (October 1, 2003): 53–71. http://dx.doi.org/10.1042/bse0390053.
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Death receptors [Fas/Apo-1/CD95, TNF-R1 [tumour necrosis factor (TNF) receptor 1], DR3 [death receptor 3], TRAIL-R1 [TNF-related apoptosis-inducing ligand receptor 1], TRAIL-R2, DR6, p75-NGFR [p75-nerve growth factor receptor], EDAR [ectodermal dysplasia receptor]] form a subgroup of the TNF-R superfamily that can induce apoptosis (programmed cell death) via a conserved cytoplasmic signalling module termed the death domain. Although death receptors have been recognized mainly as apoptosis inducers, there is growing evidence that these receptors also fulfil a variety of nonapoptotic functions. This review is focused on the molecular mechanisms of apoptotic and non-apoptotic death receptor signalling in light of the phenotype of mice deficient in the various death receptors.
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Thomas, Lance R., Ronald L. Johnson, John C. Reed, and Andrew Thorburn. "The C-terminal Tails of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) and Fas Receptors Have Opposing Functions in Fas-associated Death Domain (FADD) Recruitment and Can Regulate Agonist-specific Mechanisms of Receptor Activation." Journal of Biological Chemistry 279, no. 50 (September 27, 2004): 52479–86. http://dx.doi.org/10.1074/jbc.m409578200.
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Members of the tumor necrosis factor (TNF) superfamily of receptors such as Fas/CD95 and the TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5 induce apoptosis by recruiting adaptor molecules and caspases. The central adaptor molecule for these receptors is a death domain-containing protein, FADD, which binds to the activated receptor via death domain-death domain interactions. Here, we show that in addition to the death domain, the C-terminal tails of DR4 and DR5 positively regulate FADD binding, caspase activation and apoptosis. In contrast, the corresponding region in the Fas receptor has the opposite effect and inhibits binding to the receptor death domain. Replacement of wild-type or mutant DR5 molecules into DR5-deficient BJAB cells indicates that some agonistic antibodies display an absolute requirement for the C-terminal tail for FADD binding and signaling while other antibodies can function in the absence of this mechanism. These data demonstrate that regions outside the death domains of DR4 and DR5 have opposite effects to that of Fas in regulating FADD recruitment and show that different death receptor agonists can use distinct molecular mechanisms to activate signaling from the same receptor.
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Foley, Caitlin J., Holly Freedman, Sheryl L. Choo, Christina Onyskiw, Nai Yang Fu, Victor C. Yu, Jack Tuszynski, Joanne C. Pratt, and Shairaz Baksh. "Dynamics of RASSF1A/MOAP-1 Association with Death Receptors." Molecular and Cellular Biology 28, no. 14 (May 12, 2008): 4520–35. http://dx.doi.org/10.1128/mcb.02011-07.
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ABSTRACT RASSF1A is a tumor suppressor protein involved in death receptor-dependent apoptosis utilizing the Bax-interacting protein MOAP-1 (previously referred to as MAP-1). However, the dynamics of death receptor recruitment of RASSF1A and MOAP-1 are still not understood. We have now detailed recruitment to death receptors (tumor necrosis factor receptor 1 [TNF-R1] and TRAIL-R1/DR4) and identified domains of RASSF1A and MOAP-1 that are required for death receptor interaction. Upon TNF-α stimulation, the C-terminal region of MOAP-1 associated with the death domain of TNF-R1; subsequently, RASSF1A was recruited to MOAP-1/TNF-R1 complexes. Prior to recruitment to TNF-R1/MOAP-1 complexes, RASSF1A homodimerization was lost. RASSF1A associated with the TNF-R1/MOAP-1 or TRAIL-R1/MOAP-1 complex via its N-terminal cysteine-rich (C1) domain containing a potential zinc finger binding motif. Importantly, TNF-R1 association domains on both MOAP-1 and RASSF1A were essential for death receptor-dependent apoptosis. The association of RASSF1A and MOAP-1 with death receptors involves an ordered recruitment to receptor complexes to promote cell death and inhibit tumor formation.
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Brojatsch, Jürgen, John Naughton, Heather B. Adkins, and John A. T. Young. "TVB Receptors for Cytopathic and Noncytopathic Subgroups of Avian Leukosis Viruses Are Functional Death Receptors." Journal of Virology 74, no. 24 (December 15, 2000): 11490–94. http://dx.doi.org/10.1128/jvi.74.24.11490-11494.2000.
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ABSTRACT The identification of TVBS3, a cellular receptor for the cytopathic subgroups B and D of avian leukosis virus (ALV-B and ALV-D), as a tumor necrosis factor receptor-related death receptor with a cytoplasmic death domain, provides a compelling argument that viral Env-receptor interactions are linked to cell death (4). However, other TVB proteins have been described that appear to have similar death domains but are cellular receptors for the noncytopathic subgroup E of ALV (ALV-E): TVBT, a turkey subgroup E-specific ALV receptor, and TVBS1, a chicken receptor for subgroups B, D, and E ALV. To begin to understand the role of TVB receptors in the cytopathic effects associated with infection by specific ALV subgroups, we asked whether binding of a soluble ALV-E surface envelope protein (SU) to its receptor can lead to cell death. Here we report that ALV-E SU-receptor interactions can induce apoptosis in quail or turkey cells. We also show directly that TVBS1and TVBT are functional death receptors that can trigger cell death by apoptosis via a mechanism involving their cytoplasmic death domains and activation of the caspase pathway. These data demonstrate that ALV-B and ALV-E use functional death receptors to enter cells, and it remains to be determined why only subgroups B and D viral infections lead specifically to cell death.
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Denecker, G., D. Vercammen, W. Declercq, and P. Vandenabeele. "Apoptotic and necrotic cell death induced by death domain receptors." Cellular and Molecular Life Sciences 58, no. 3 (March 2001): 356–70. http://dx.doi.org/10.1007/pl00000863.
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Varfolomeev, E. E., M. P. Boldin, T. M. Goncharov, and D. Wallach. "A potential mechanism of "cross-talk" between the p55 tumor necrosis factor receptor and Fas/APO1: proteins binding to the death domains of the two receptors also bind to each other." Journal of Experimental Medicine 183, no. 3 (March 1, 1996): 1271–75. http://dx.doi.org/10.1084/jem.183.3.1271.
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The p55 tumor necrosis factor (TNF) receptor and Fas/APO1 induce cell death via distinct regions in their intracellular domains. Three cytoplasmic proteins that bind to these receptor regions have been identified recently. One, MORT1 (also called FADD), binds to Fas/APO1 but not to p55-R; another, TRADD, binds to the p55 TNF receptor but not to Fas/APO1; and the third, RIP, binds weakly to both receptors. The regions within these proteins that are involved in binding to the receptors and the receptor regions to which they bind share a common sequence motif, that of the "death domain." This study shows that the death domain motifs in MORT1, TRADD, and RIP bind effectively to each other, a mode of binding that may allow "cross-talk" between the functional expression of the p55 TNF receptor and Fas/APO1.
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Gao, Yin, Xue Luan, Jacob Melamed, and Inka Brockhausen. "Role of Glycans on Key Cell Surface Receptors That Regulate Cell Proliferation and Cell Death." Cells 10, no. 5 (May 19, 2021): 1252. http://dx.doi.org/10.3390/cells10051252.
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Cells undergo proliferation and apoptosis, migration and differentiation via a number of cell surface receptors, most of which are heavily glycosylated. This review discusses receptor glycosylation and the known roles of glycans on the functions of receptors expressed in diverse cell types. We included growth factor receptors that have an intracellular tyrosine kinase domain, growth factor receptors that have a serine/threonine kinase domain, and cell-death-inducing receptors. N- and O-glycans have a wide range of functions including roles in receptor conformation, ligand binding, oligomerization, and activation of signaling cascades. A better understanding of these functions will enable control of cell survival and cell death in diseases such as cancer and in immune responses.
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Zhang, Xiaoxiao, Maud Bernoux, Adam R. Bentham, Toby E. Newman, Thomas Ve, Lachlan W. Casey, Tom M. Raaymakers, et al. "Multiple functional self-association interfaces in plant TIR domains." Proceedings of the National Academy of Sciences 114, no. 10 (February 3, 2017): E2046—E2052. http://dx.doi.org/10.1073/pnas.1621248114.
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The self-association of Toll/interleukin-1 receptor/resistance protein (TIR) domains has been implicated in signaling in plant and animal immunity receptors. Structure-based studies identified different TIR-domain dimerization interfaces required for signaling of the plant nucleotide-binding oligomerization domain-like receptors (NLRs) L6 from flax and disease resistance protein RPS4 fromArabidopsis. Here we show that the crystal structure of the TIR domain from theArabidopsisNLR suppressor of npr1-1, constitutive 1 (SNC1) contains both an L6-like interface involving helices αD and αE (DE interface) and an RPS4-like interface involving helices αA and αE (AE interface). Mutations in either the AE- or DE-interface region disrupt cell-death signaling activity of SNC1, L6, and RPS4 TIR domains and full-length L6 and RPS4. Self-association of L6 and RPS4 TIR domains is affected by mutations in either region, whereas only AE-interface mutations affect SNC1 TIR-domain self-association. We further show two similar interfaces in the crystal structure of the TIR domain from theArabidopsisNLR recognition ofPeronospora parasitica1 (RPP1). These data demonstrate that both the AE and DE self-association interfaces are simultaneously required for self-association and cell-death signaling in diverse plant NLRs.
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Essuman, Kow, Li Wan, Daniel W. Summers, Ryan G. Anderson, Yo Sasaki, Xianrong Mao, Aldrin Kay Yuen Yim, et al. "Redefining the TIR domain: From Axon Degeneration to Innate Immunity and Beyond." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 64.1. http://dx.doi.org/10.4049/jimmunol.202.supp.64.1.
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Abstract The Toll/Interleukin-1 Receptor (TIR) domain is an evolutionary ancient protein domain, present in numerous receptors and adaptor proteins, and is the signature-signaling domain of Toll-Like Receptors (TLRs). In animals, these TIR domains generally serve as scaffolds that promote the assembly of signaling complexes to trigger activation of pro-inflammatory cytokines and other defense-related products. In plants, TIR domain proteins are known to mediate disease resistance against pathogens, and trigger hypersensitive cell death. However, their mechanism of action has remained elusive. In bacteria, TIR domains have been associated with virulence and defense against some viruses. Here, we redefine the canonical scaffolding function of the TIR domain by showing that TIR domains can possess intrinsic enzymatic activity, and constitute a family of enzymes that cleave the essential metabolic cofactor Nicotinamide Adenine Dinucleotide (NAD+). We identify the TIR domain of SARM1 as the founding member of the TIR NADase family that triggers axon self-destruction upon axonal injury. We show that the TIR enzymatic activity in conserved in bacteria, and archaea, where in bacteria this NADase activity has recently been linked to defense against viruses. Finally, we extend our findings to plant innate immunity, and show that plant TIR-domain Immune Receptors trigger cell death and transduce recognition of pathogens into an immune response via this conserved enzymatic activity. Altogether, our findings establish TIR domain proteins as a new family of metabolic enzymes, and we posit that the scaffolding function in TLR signaling likely represents a repurposing of this evolutionary ancient enzymatic function.
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Thorburn, Jacqueline, Laura M. Bender, Michael J. Morgan, and Andrew Thorburn. "Caspase- and Serine Protease-dependent Apoptosis by the Death Domain of FADD in Normal Epithelial Cells." Molecular Biology of the Cell 14, no. 1 (January 2003): 67–77. http://dx.doi.org/10.1091/mbc.e02-04-0207.
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The adapter protein FADD consists of two protein interaction domains: a death domain and a death effector domain. The death domain binds to activated death receptors such as Fas, whereas the death effector domain binds to procaspase 8. An FADD mutant, which consists of only the death domain (FADD-DD), inhibits death receptor–induced apoptosis. FADD-DD can also activate a mechanistically distinct, cell type–specific apoptotic pathway that kills normal but not cancerous prostate epithelial cells. Here, we show that this apoptosis occurs through activation of caspases 9, 3, 6, and 7 and a serine protease. Simultaneous inhibition of caspases and serine proteases prevents FADD-DD–induced death. Inhibition of either pathway alone does not prevent cell death but does affect the morphology of the dying cells. Normal prostate epithelial cells require both the caspase and serine protease inhibitors to efficiently prevent apoptosis in response to TRAIL. In contrast, the serine protease inhibitor does not affect TRAIL-induced death in prostate tumor cells suggesting that the FADD-DD–dependent pathway can be activated by TRAIL. This apoptosis pathway is activated in a cell type–specific manner that is defective in cancer cells, suggesting that this pathway may be targeted during cancer development.
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Bi, Guozhi, and Jian-Min Zhou. "Regulation of Cell Death and Signaling by Pore-Forming Resistosomes." Annual Review of Phytopathology 59, no. 1 (August 25, 2021): 239–63. http://dx.doi.org/10.1146/annurev-phyto-020620-095952.
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Nucleotide-binding leucine-rich repeat receptors (NLRs) are the largest class of immune receptors in plants. They play a key role in the plant surveillance system by monitoring pathogen effectors that are delivered into the plant cell. Recent structural biology and biochemical analyses have uncovered how NLRs are activated to form oligomeric resistosomes upon the recognition of pathogen effectors. In the resistosome, the signaling domain of the NLR is brought to the center of a ringed structure to initiate immune signaling and regulated cell death (RCD). The N terminus of the coiled-coil (CC) domain of the NLR protein HOPZ-ACTIVATED RESISTANCE 1 likely forms a pore in the plasma membrane to trigger RCD in a way analogous to animal pore-forming proteins that trigger necroptosis or pyroptosis. NLRs that carry TOLL-INTERLEUKIN1-RECEPTOR as a signaling domain may also employ pore-forming resistosomes for RCD execution. In addition, increasing evidence supports intimate connections between NLRs and surface receptors in immune signaling. These new findings are rapidly advancing our understanding of the plant immune system.
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Mongkolsapaya, Juthathip, Alison E. Cowper, Xiao-Ning Xu, Gwilym Morris, Andrew J. McMichael, John I. Bell, and Gavin R. Screaton. "Cutting Edge: Lymphocyte Inhibitor of TRAIL (TNF-Related Apoptosis-Inducing Ligand): A New Receptor Protecting Lymphocytes from the Death Ligand TRAIL." Journal of Immunology 160, no. 1 (January 1, 1998): 3–6. http://dx.doi.org/10.4049/jimmunol.160.1.3.
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Abstract Apoptosis can be triggered by the engagement of cell surface receptors by their ligands. A growing number of receptors belonging to the TNF receptor family have been identified that contain a conserved cytoplasmic death domain. These include Fas, TNF-R1, lymphocyte-associated receptor of death (LARD), DR4, and TNF-related apoptosis-inducing ligand receptor inducer of cell killing-2 (TRICK2). The latter two are receptors for the cytotoxic ligand TNF-related apoptosis-inducing ligand (TRAIL), and one of the paradoxes raised by the cloning of these molecules was why do most cells not die upon contact with the widely expressed TRAIL molecule? This is a particular problem for lymphocytes that express DR4 and TRICK2 and are in constant circulation through TRAIL-expressing tissues. We have cloned LIT (lymphocyte inhibitor of TRAIL), which lacks a death domain. LIT is expressed predominantly on PBL, where it can competitively inhibit TRAIL-induced apoptosis through DR4/TRICK2, and may function to modulate lymphocyte sensitivity to TRAIL.
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Moriwaki, Kenta, Francis K. M. Chan, and Eiji Miyoshi. "Sweet modification and regulation of death receptor signalling pathway." Journal of Biochemistry 169, no. 6 (March 22, 2021): 643–52. http://dx.doi.org/10.1093/jb/mvab034.
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Abstract Death receptors, members of the tumour necrosis factor receptor (TNFR) superfamily, are characterized by the presence of a death domain in the cytosolic region. TNFR1, Fas and TNF-related apoptosis-inducing ligand receptors, which are prototypical death receptors, exert pleiotropic functions in cell death, inflammation and immune surveillance. Hence, they are involved in several human diseases. The activation of death receptors and downstream intracellular signalling is regulated by various posttranslational modifications, such as phosphorylation, ubiquitination and glycosylation. Glycosylation is one of the most abundant and versatile modifications to proteins and lipids, and it plays a critical role in the development and physiology of organisms, as well as the pathology of many human diseases. Glycans control a number of cellular events, such as receptor activation, signal transduction, endocytosis, cell recognition and cell adhesion. It has been demonstrated that oligo- and monosaccharides modify death receptors and intracellular signalling proteins and regulate their functions. Here, we review the current understanding of glycan modifications of death receptor signalling and their impact on signalling activity.
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Klucking, Sara, Asha S. Collins, and John A. T. Young. "Avian Sarcoma and Leukosis Virus Cytopathic Effect in the Absence of TVB Death Domain Signaling." Journal of Virology 79, no. 13 (July 1, 2005): 8243–48. http://dx.doi.org/10.1128/jvi.79.13.8243-8248.2005.
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ABSTRACT The cytopathic effect (CPE) seen with some subgroups of avian sarcoma and leukosis virus (ASLV) is associated with viral Env activation of the death-promoting activity of TVB (a tumor necrosis factor receptor-related receptor that is most closely related to mammalian TNF-related apoptosis-inducing ligand [TRAIL] receptors) and with viral superinfection leading to unintegrated viral DNA (UVD) accumulation, which is presumed to activate a cellular DNA damage response. In this study, we employed cells that express signaling-deficient ASLV receptors to demonstrate that an ASLV CPE can be uncoupled from the death-promoting functions of the TVB receptor. However, these cell-killing events were associated with much higher levels of viral superinfection and DNA accumulation than those seen when the virus used signaling-competent TVB receptors. These findings suggest that a putative cellular DNA damage response that is activated by UVD accumulation might act in concert with the death-signaling pathways activated by Env-TVB interactions to trigger cell death. Such a model is consistent with the well-established synergy that exists between TRAIL-signaling pathways and DNA damage responses which is currently being exploited in cancer therapy regimens.
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Eibl, Clarissa, Manuel Hessenberger, Julia Wenger, and Hans Brandstetter. "Structures of the NLRP14 pyrin domain reveal a conformational switch mechanism regulating its molecular interactions." Acta Crystallographica Section D Biological Crystallography 70, no. 7 (June 29, 2014): 2007–18. http://dx.doi.org/10.1107/s1399004714010311.
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The cytosolic tripartite NLR receptors serve as important signalling platforms in innate immunity. While the C-terminal domains act as sensor and activation modules, the N-terminal death-like domain,e.g.the CARD or pyrin domain, is thought to recruit downstream effector molecules by homotypic interactions. Such homotypic complexes have been determined for all members of the death-domain superfamily except for pyrin domains. Here, crystal structures of human NLRP14 pyrin-domain variants are reported. The wild-type protein as well as the clinical D86V mutant reveal an unexpected rearrangement of the C-terminal helix α6, resulting in an extended α5/6 stem-helix. This reordering mediates a novel symmetric pyrin-domain dimerization mode. The conformational switching is controlled by a charge-relay system with a drastic impact on protein stability. How the identified charge relay allows classification of NLRP receptors with respect to distinct recruitment mechanisms is discussed.
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Mongiat, Maurizio, Giovanni Ligresti, Stefano Marastoni, Erica Lorenzon, Roberto Doliana, and Alfonso Colombatti. "Regulation of the Extrinsic Apoptotic Pathway by the Extracellular Matrix Glycoprotein EMILIN2." Molecular and Cellular Biology 27, no. 20 (August 13, 2007): 7176–87. http://dx.doi.org/10.1128/mcb.00696-07.
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ABSTRACT Elastin microfibril interface-located proteins (EMILINs) constitute a family of extracellular matrix (ECM) glycoproteins characterized by the presence of an EMI domain at the N terminus and a gC1q domain at the C terminus. EMILIN1, the archetype molecule of the family, is involved in elastogenesis and hypertension etiology, whereas the function of EMILIN2 has not been resolved. Here, we provide evidence that the expression of EMILIN2 triggers the apoptosis of different cell lines. Cell death depends on the activation of the extrinsic apoptotic pathway following EMILIN2 binding to the TRAIL receptors DR4 and, to a lesser extent, DR5. Binding is followed by receptor clustering, colocalization with lipid rafts, death-inducing signaling complex assembly, and caspase activation. The direct activation of death receptors by an ECM molecule that mimics the activity of the known death receptor ligands is novel. The knockdown of EMILIN2 increases transformed cell survival, and overexpression impairs clonogenicity in soft agar and three-dimensional growth in natural matrices due to massive apoptosis. These data demonstrate an unexpected direct and functional interaction of an ECM constituent with death receptors and discloses an additional mechanism by which ECM cues can negatively affect cell survival.
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Okuda, K., A. D’Andrea, R. A. Van Etten, and J. D. Griffin. "The C-Terminus of c-Abl Is Required for Proliferation and Viability Signaling in a c-Abl/Erythropoietin Receptor Fusion Protein." Blood 92, no. 10 (November 15, 1998): 3848–56. http://dx.doi.org/10.1182/blood.v92.10.3848.
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Abstract Activated ABL oncogenes cause B-cell leukemias in mice and chronic myelogenous leukemia in humans. However, the mechanism of transformation is complex and not well understood. A method to rapidly and reversibly activate c-ABL was created by fusing the extra-cytoplasmic and transmembrane domain of the erythropoietin (EPO) receptor with c-ABL (EPO R/ABL). When this chimeric receptor was expressed in Ba/F3 cells, the addition of EPO resulted in a dose-dependent activation of c-ABL tyrosine kinase and was strongly antiapoptotic and weakly mitogenic. To evaluate the contributions of various ABL domains to biochemical signaling and biological effects, chimeric receptors were constructed in which the ABL SH3 domain was deleted (▵SH3), the SH2 domain was deleted (▵SH2), the C-terminal actin-binding domain was deleted (▵ABD), or kinase activity was eliminated by a point mutation, K290M (KD). The mutant receptors were stably expressed in Ba/F3 cells and analyzed for signaling defects, proliferation, viability, and EPO-induced leukemia in nude mice. When compared with the ability of the full-length EPO R/ABL receptor to induce proliferation and support viability in vitro, the ▵SH3 mutant was equivalent, the ▵SH2 mutant was moderately impaired, and the ▵ABD and KD mutants were profoundly impaired. None of these cell lines caused leukemia in mice in the absence of pharmacological doses of EPO. However, in mice treated with EPO (10 U/d), death from leukemia occurred rapidly with wild-type and ▵SH3. However, time to death was prolonged by at least twofold for ▵SH2 and greater than threefold for ▵ABD. This inducible model of ABL transformation provides a method to link specific signaling defects with specific biological defects and has shown an important role for the C-terminal actin-binding domain in proliferation and transformation in the context of this receptor/oncogene.
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Okuda, K., A. D’Andrea, R. A. Van Etten, and J. D. Griffin. "The C-Terminus of c-Abl Is Required for Proliferation and Viability Signaling in a c-Abl/Erythropoietin Receptor Fusion Protein." Blood 92, no. 10 (November 15, 1998): 3848–56. http://dx.doi.org/10.1182/blood.v92.10.3848.422k44_3848_3856.
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Activated ABL oncogenes cause B-cell leukemias in mice and chronic myelogenous leukemia in humans. However, the mechanism of transformation is complex and not well understood. A method to rapidly and reversibly activate c-ABL was created by fusing the extra-cytoplasmic and transmembrane domain of the erythropoietin (EPO) receptor with c-ABL (EPO R/ABL). When this chimeric receptor was expressed in Ba/F3 cells, the addition of EPO resulted in a dose-dependent activation of c-ABL tyrosine kinase and was strongly antiapoptotic and weakly mitogenic. To evaluate the contributions of various ABL domains to biochemical signaling and biological effects, chimeric receptors were constructed in which the ABL SH3 domain was deleted (▵SH3), the SH2 domain was deleted (▵SH2), the C-terminal actin-binding domain was deleted (▵ABD), or kinase activity was eliminated by a point mutation, K290M (KD). The mutant receptors were stably expressed in Ba/F3 cells and analyzed for signaling defects, proliferation, viability, and EPO-induced leukemia in nude mice. When compared with the ability of the full-length EPO R/ABL receptor to induce proliferation and support viability in vitro, the ▵SH3 mutant was equivalent, the ▵SH2 mutant was moderately impaired, and the ▵ABD and KD mutants were profoundly impaired. None of these cell lines caused leukemia in mice in the absence of pharmacological doses of EPO. However, in mice treated with EPO (10 U/d), death from leukemia occurred rapidly with wild-type and ▵SH3. However, time to death was prolonged by at least twofold for ▵SH2 and greater than threefold for ▵ABD. This inducible model of ABL transformation provides a method to link specific signaling defects with specific biological defects and has shown an important role for the C-terminal actin-binding domain in proliferation and transformation in the context of this receptor/oncogene.
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Gajate, Consuelo, and Faustino Mollinedo. "Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts." Blood 109, no. 2 (September 26, 2006): 711–19. http://dx.doi.org/10.1182/blood-2006-04-016824.
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Abstract Multiple myeloma (MM) is an incurable B-cell malignancy, requiring new therapeutic strategies. We have found that synthetic alkyl-lysophospholipids (ALPs) edelfosine and perifosine induced apoptosis in MM cell lines and patient MM cells, whereas normal B and T lymphocytes were spared. ALPs induced recruitment of Fas/CD95 death receptor, Fas-associated death domain–containing protein, and procaspase-8 into lipid rafts, leading to the formation of the death-inducing signaling complex (DISC) and apoptosis. TNF-related apoptosis-inducing ligand receptor-1/death receptor 4 (TRAIL-R1/DR4) and TRAIL-R2/DR5, as well as Bid, were also recruited into lipid rafts, linking death receptor and mitochondrial signaling pathways. ALPs induced mitochondrial cytochrome c release. Bcl-XL overexpression prevented cytochrome c release and apoptosis. A Fas/CD95-deficient MM subline expressing DR4 and DR5 was resistant to edelfosine. Fas/CD95 retrovirus transduction bestowed edelfosine sensitivity in these cells. A Fas/CD95 mutant lacking part of the intracellular domain was ineffective. Lipid raft disruption prevented ALP-induced Fas/CD95 clustering, DISC formation, and apoptosis. ALP-induced apoptosis was Fas/CD95 ligand (FasL/CD95L) independent. ALP-induced recruitment of death receptors in lipid rafts potentiated MM cell killing by FasL/CD95L and TRAIL. These data uncover a novel lipid raft–mediated therapy in MM involving concentration of death receptors in membrane rafts, with Fas/CD95 playing a major role in ALP-mediated apoptosis.
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Kurenova, Elena, Li-Hui Xu, Xihui Yang, Albert S. Baldwin, Rolf J. Craven, Steven K. Hanks, Zheng-gang Liu, and William G. Cance. "Focal Adhesion Kinase Suppresses Apoptosis by Binding to the Death Domain of Receptor-Interacting Protein." Molecular and Cellular Biology 24, no. 10 (May 15, 2004): 4361–71. http://dx.doi.org/10.1128/mcb.24.10.4361-4371.2004.
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ABSTRACT Tumor cells resist the apoptotic stimuli associated with invasion and metastasis by activating survival signals that suppress apoptosis. Focal adhesion kinase (FAK), a tyrosine kinase that is overexpressed in a variety of human tumors, mediates one of these survival signals. Attenuation of FAK expression in tumor cells results in apoptosis that is mediated by caspase 8- and FADD-dependent pathways, suggesting that death receptor pathways are involved in the process. Here, we report a functional link between FAK and death receptors. We have demonstrated that FAK binds to the death domain kinase receptor-interacting protein (RIP). RIP is a major component of the death receptor complex and has been shown to interact with Fas and tumor necrosis factor receptor 1 through its binding to adapter proteins. We have shown that RIP provides proapoptotic signals that are suppressed by its binding to FAK. We thus propose that FAK overexpression in human tumors provides a survival signal function by binding to RIP and inhibiting its interaction with the death receptor complex.
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Siegel, Richard M., David A. Martin, Lixin Zheng, Samuel Y. Ng, John Bertin, Jeffrey Cohen, and Michael J. Lenardo. "Death-effector Filaments: Novel Cytoplasmic Structures that Recruit Caspases and Trigger Apoptosis." Journal of Cell Biology 141, no. 5 (June 1, 1998): 1243–53. http://dx.doi.org/10.1083/jcb.141.5.1243.
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The death-effector domain (DED) is a critical protein interaction domain that recruits caspases into complexes with members of the TNF-receptor superfamily. Apoptosis can also be induced by expressing certain DED-containing proteins without surface receptor cross-linking. Using Green Fluorescent Protein to examine DED-containing proteins in living cells, we show that these proteins cause apoptosis by forming novel cytoplasmic filaments that recruit and activate pro-caspase zymogens. Formation of these filaments, which we term death-effector filaments, was blocked by coexpression of viral antiapoptotic DED-containing proteins, but not by bcl-2 family proteins. Thus, formation of death-effector filaments allows a regulated intracellular assembly of apoptosis-signaling complexes that can initiate or amplify apoptotic stimuli independently of receptors at the plasma membrane.
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Tollefson, Ann E., Karoly Toth, Konstantin Doronin, Mohan Kuppuswamy, Oksana A. Doronina, Drew L. Lichtenstein, Terry W. Hermiston, Craig A. Smith, and William S. M. Wold. "Inhibition of TRAIL-Induced Apoptosis and Forced Internalization of TRAIL Receptor 1 by Adenovirus Proteins." Journal of Virology 75, no. 19 (October 1, 2001): 8875–87. http://dx.doi.org/10.1128/jvi.75.19.8875-8887.2001.
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ABSTRACT Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis through two receptors, TRAIL-R1 (also known as death receptor 4) and TRAIL-R2 (also known as death receptor 5), that are members of the TNF receptor superfamily of death domain-containing receptors. We show that human adenovirus type 5 encodes three proteins, named RID (previously named E3-10.4K/14.5K), E3-14.7K, and E1B-19K, that independently inhibit TRAIL-induced apoptosis of infected human cells. This conclusion was derived from studies using wild-type adenovirus, adenovirus replication-competent mutants that lack one or more of the RID,E3-14.7K, and E1B-19K genes, and adenovirus E1-minus replication-defective vectors that express all E3 genes, RID plus E3-14.7K only, RID only, or E3-14.7K only. RID inhibits TRAIL-induced apoptosis when cells are sensitized to TRAIL either by adenovirus infection or treatment with cycloheximide. RID induces the internalization of TRAIL-R1 from the cell surface, as shown by flow cytometry and indirect immunofluorescence for TRAIL-R1. TRAIL-R1 was internalized in distinct vesicles which are very likely to be endosomes and lysosomes. TRAIL-R1 is degraded, as indicated by the disappearance of the TRAIL-R1 immunofluorescence signal. Degradation was inhibited by bafilomycin A1, a drug that prevents acidification of vesicles and the sorting of receptors from late endosomes to lysosomes, implying that degradation occurs in lysosomes. RID was also shown previously to internalize and degrade another death domain receptor, Fas, and to prevent apoptosis through Fas and the TNF receptor. RID was shown previously to force the internalization and degradation of the epidermal growth factor receptor. E1B-19K was shown previously to block apoptosis through Fas, and both E1B-19K and E3-14.7K were found to prevent apoptosis through the TNF receptor. These findings suggest that the receptors for TRAIL, Fas ligand, and TNF play a role in limiting virus infections. The ability of adenovirus to inhibit killing through these receptors may prolong acute and persistent infections.
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Bolus, Stephen, Eduard Akhunov, Gitta Coaker, and Jorge Dubcovsky. "Dissection of Cell Death Induction by Wheat Stem Rust Resistance Protein Sr35 and Its Matching Effector AvrSr35." Molecular Plant-Microbe Interactions® 33, no. 2 (February 2020): 308–19. http://dx.doi.org/10.1094/mpmi-08-19-0216-r.
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Nucleotide-binding leucine-rich repeat receptors (NLRs) are the most abundant type of immune receptors in plants and can trigger a rapid cell-death (hypersensitive) response upon sensing pathogens. We previously cloned the wheat NLR Sr35, which encodes a coiled-coil (CC) NLR that confers resistance to the virulent wheat stem rust race Ug99. Here, we investigated Sr35 signaling after Agrobacterium-mediated transient expression in Nicotiana benthamiana. Expression of Sr35 in N. benthamiana leaves triggered a mild cell-death response, which is enhanced in the autoactive mutant Sr35 D503V. The N-terminal tagging of Sr35 with green fluorescent protein (GFP) blocked the induction of cell death, whereas a C-terminal GFP tag did not. No domain truncations of Sr35 generated cell-death responses as strong as the wild type, but a truncation including the NB-ARC (nucleotide binding adaptor) shared by APAF-1, R proteins, and CED-4 domains in combination with the D503V autoactive mutation triggered cell death. In addition, coexpression of Sr35 with the matching pathogen effector protein AvrSr35 resulted in robust cell death and electrolyte leakage levels that were similar to autoactive Sr35 and significantly higher than Sr35 alone. Coexpression of Sr35-CC-NB-ARC and AvrSr35 did not induce cell death, confirming the importance of the leucine-rich repeat (LRR) domain for AvrSr35 recognition. These findings were confirmed through Agrobacterium-mediated transient expression in barley. Taken together, these results implicate the CC-NB-ARC domains of Sr35 in inducing cell death and the LRR domain in AvrSr35 recognition. [Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
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COHEN, Gerald M. "Caspases: the executioners of apoptosis." Biochemical Journal 326, no. 1 (August 15, 1997): 1–16. http://dx.doi.org/10.1042/bj3260001.
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Apoptosis is a major form of cell death, characterized initially by a series of stereotypic morphological changes. In the nematode Caenorhabditis elegans, the gene ced-3 encodes a protein required for developmental cell death. Since the recognition that CED-3 has sequence identity with the mammalian cysteine protease interleukin-1β-converting enzyme (ICE), a family of at least 10 related cysteine proteases has been identified. These proteins are characterized by almost absolute specificity for aspartic acid in the P1 position. All the caspases (ICE-like proteases) contain a conserved QACXG (where X is R, Q or G) pentapeptide active-site motif. Caspases are synthesized as inactive proenzymes comprising an N-terminal peptide (prodomain) together with one large and one small subunit. The crystal structures of both caspase-1 and caspase-3 show that the active enzyme is a heterotetramer, containing two small and two large subunits. Activation of caspases during apoptosis results in the cleavage of critical cellular substrates, including poly(ADP-ribose) polymerase and lamins, so precipitating the dramatic morphological changes of apoptosis. Apoptosis induced by CD95 (Fas/APO-1) and tumour necrosis factor activates caspase-8 (MACH/FLICE/Mch5), which contains an N-terminus with FADD (Fas-associating protein with death domain)-like death effector domains, so providing a direct link between cell death receptors and the caspases. The importance of caspase prodomains in the regulation of apoptosis is further highlighted by the recognition of adapter molecules, such as RAIDD [receptor-interacting protein (RIP)-associated ICH-1/CED-3-homologous protein with a death domain]/CRADD (caspase and RIP adapter with death domain), which binds to the prodomain of caspase-2 and recruits it to the signalling complex. Cells undergoing apoptosis following triggering of death receptors execute the death programme by activating a hierarchy of caspases, with caspase-8 and possibly caspase-10 being at or near the apex of this apoptotic cascade.
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Cao, Peng, Wenting Zhang, Wenjun Gui, Yuhui Dong, Tao Jiang, and Yong Gong. "Structural insights into the mechanism of calmodulin binding to death receptors." Acta Crystallographica Section D Biological Crystallography 70, no. 6 (May 24, 2014): 1604–13. http://dx.doi.org/10.1107/s1399004714006919.
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The death receptors Fas, p75NTRand DR6 are key components of extrinsically activated apoptosis. Characterization of how they interact with the adaptors is crucial in order to unravel the signalling mechanisms. However, the exact conformation that their intracellular death domain adopts upon binding downstream partners remains unclear. One model suggests that it adopts a typical compact fold, whilst a second model proposed an open conformation. Calmodulin (CaM), a major calcium sensor, has previously been reported to be one of the Fas adaptors that modulate apoptosis. This work reports that CaM also binds directly to the death domains of p75NTRand DR6, indicating that it serves as a common modulator of the death receptors. Two crystal structures of CaM in complexes with the corresponding binding regions of Fas and p75NTRare also reported. Interestingly, the precise CaM-binding sites were mapped to different regions: helix 1 in Fas and helix 5 in p75NTRand DR6. A novel 1–11 motif for CaM binding was observed in p75NTR. Modelling the complexes of CaM with full-length receptors reveals that the opening of the death domains would be essential in order to expose their binding sites for CaM. These results may facilitate understanding of the diverse functional repertoire of death receptors and CaM and provide further insights necessary for the design of potential therapeutic peptide agents.
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Horsefield, Shane, Hayden Burdett, Xiaoxiao Zhang, Mohammad K. Manik, Yun Shi, Jian Chen, Tiancong Qi, et al. "NAD+ cleavage activity by animal and plant TIR domains in cell death pathways." Science 365, no. 6455 (August 22, 2019): 793–99. http://dx.doi.org/10.1126/science.aax1911.
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SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD+) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association–dependent NAD+ cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP+ (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD+ cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.
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Motta, Vinicius, Fraser Soares, Tian Sun, and Dana J. Philpott. "NOD-Like Receptors: Versatile Cytosolic Sentinels." Physiological Reviews 95, no. 1 (January 2015): 149–78. http://dx.doi.org/10.1152/physrev.00009.2014.
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Nucleotide binding oligomerization domain (NOD)-like receptors are cytoplasmic pattern-recognition receptors that together with RIG-I-like receptor (retinoic acid-inducible gene 1), Toll-like receptor (TLR), and C-type lectin families make up the innate pathogen pattern recognition system. There are 22 members of NLRs in humans, 34 in mice, and even a larger number in some invertebrates like sea urchins, which contain more than 200 receptors. Although initially described to respond to intracellular pathogens, NLRs have been shown to play important roles in distinct biological processes ranging from regulation of antigen presentation, sensing metabolic changes in the cell, modulation of inflammation, embryo development, cell death, and differentiation of the adaptive immune response. The diversity among NLR receptors is derived from ligand specificity conferred by the leucine-rich repeats and an NH2-terminal effector domain that triggers the activation of different biological pathways. Here, we describe NLR genes associated with different biological processes and the molecular mechanisms underlying their function. Furthermore, we discuss mutations in NLR genes that have been associated with human diseases.
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Heller, Jens, Corinne Clavé, Pierre Gladieux, Sven J. Saupe, and N. Louise Glass. "NLR surveillance of essential SEC-9 SNARE proteins induces programmed cell death upon allorecognition in filamentous fungi." Proceedings of the National Academy of Sciences 115, no. 10 (February 20, 2018): E2292—E2301. http://dx.doi.org/10.1073/pnas.1719705115.
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In plants and metazoans, intracellular receptors that belong to the NOD-like receptor (NLR) family are major contributors to innate immunity. Filamentous fungal genomes contain large repertoires of genes encoding for proteins with similar architecture to plant and animal NLRs with mostly unknown function. Here, we identify and molecularly characterize patatin-like phospholipase-1 (PLP-1), an NLR-like protein containing an N-terminal patatin-like phospholipase domain, a nucleotide-binding domain (NBD), and a C-terminal tetratricopeptide repeat (TPR) domain. PLP-1 guards the essential SNARE protein SEC-9; genetic differences at plp-1 and sec-9 function to trigger allorecognition and cell death in two distantly related fungal species, Neurospora crassa and Podospora anserina. Analyses of Neurospora population samples revealed that plp-1 and sec-9 alleles are highly polymorphic, segregate into discrete haplotypes, and show transspecies polymorphism. Upon fusion between cells bearing incompatible sec-9 and plp-1 alleles, allorecognition and cell death are induced, which are dependent upon physical interaction between SEC-9 and PLP-1. The central NBD and patatin-like phospholipase activity of PLP-1 are essential for allorecognition and cell death, while the TPR domain and the polymorphic SNARE domain of SEC-9 function in conferring allelic specificity. Our data indicate that fungal NLR-like proteins function similar to NLR immune receptors in plants and animals, showing that NLRs are major contributors to innate immunity in plants and animals and for allorecognition in fungi.
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Maekawa, Takaki, Barbara Kracher, Isabel M. L. Saur, Makoto Yoshikawa-Maekawa, Ronny Kellner, Artem Pankin, Maria von Korff, and Paul Schulze-Lefert. "Subfamily-Specific Specialization of RGH1/MLA Immune Receptors in Wild Barley." Molecular Plant-Microbe Interactions® 32, no. 1 (January 2019): 107–19. http://dx.doi.org/10.1094/mpmi-07-18-0186-fi.
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The barley disease resistance (R) gene locus mildew locus A (Mla) provides isolate-specific resistance against the powdery mildew fungus Blumeria graminis hordei and has been introgressed into modern cultivars from diverse germplasms, including the wild relative Hordeum spontaneum. Known Mla disease resistance specificities to B. graminis hordei appear to encode allelic variants of the R gene homolog 1 (RGH1) family of nucleotide-binding domain and leucine-rich repeat (NLR) proteins. Here, we sequenced and assembled the transcriptomes of 50 H. spontaneum accessions representing nine populations distributed throughout the Fertile Crescent. The assembled Mla transcripts exhibited rich sequence diversity, linked neither to geographic origin nor population structure, and could be grouped into two similar-sized subfamilies based on two major N-terminal coiled-coil (CC) signaling domains that are both capable of eliciting cell death. The presence of positively selected sites located mainly in the C-terminal leucine-rich repeats of both MLA subfamilies, together with the fact that both CC signaling domains mediate cell death, implies that the two subfamilies are actively maintained in the population. Unexpectedly, known MLA receptor variants that confer B. graminis hordei resistance belong exclusively to one subfamily. Thus, signaling domain divergence, potentially as adaptation to distinct pathogen populations, is an evolutionary signature of functional diversification of an immune receptor. [Formula: see text] Copyright © 2018 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
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Kuzevanova, Anna, Natalya Apanovich, Danzan Mansorunov, Alexandra Korotaeva, and Alexander Karpukhin. "The Features of Checkpoint Receptor—Ligand Interaction in Cancer and the Therapeutic Effectiveness of Their Inhibition." Biomedicines 10, no. 9 (August 25, 2022): 2081. http://dx.doi.org/10.3390/biomedicines10092081.
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To date, certain problems have been identified in cancer immunotherapy using the inhibition of immune checkpoints (ICs). Despite the excellent effect of cancer therapy in some cases when blocking the PD-L1 (programmed death-ligand 1) ligand and the immune cell receptors PD-1 (programmed cell death protein 1) and CTLA4 (cytotoxic T-lymphocyte-associated protein 4) with antibodies, the proportion of patients responding to such therapy is still far from desirable. This situation has stimulated the exploration of additional receptors and ligands as targets for immunotherapy. In our article, based on the analysis of the available data, the TIM-3 (T-cell immunoglobulin and mucin domain-3), LAG-3 (lymphocyte-activation gene 3), TIGIT (T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains), VISTA (V-domain Ig suppressor of T-cell activation), and BTLA (B- and T-lymphocyte attenuator) receptors and their ligands are comprehensively considered. Data on the relationship between receptor expression and the clinical characteristics of tumors are presented and are analyzed together with the results of preclinical and clinical studies on the therapeutic efficacy of their blocking. Such a comprehensive analysis makes it possible to assess the prospects of receptors of this series as targets for anticancer therapy. The expression of the LAG-3 receptor shows the most unambiguous relationship with the clinical characteristics of cancer. Its inhibition is the most effective of the analyzed series in terms of the antitumor response. The expression of TIGIT and BTLA correlates well with clinical characteristics and demonstrates antitumor efficacy in preclinical and clinical studies, which indicates their high promise as targets for anticancer therapy. At the same time, the relationship of VISTA and TIM-3 expression with the clinical characteristics of the tumor is contradictory, and the results on the antitumor effectiveness of their inhibition are inconsistent.
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Borys, Sylwia, Ronza Khozmi, Wiesława Kranc, Artur Bryja, Marta Dyszkiewicz-Konwińska, Michal Jeseta, and Bartosz Kempisty. "Recent Findings of the Types of Programmed Cell Death." Advances in Cell Biology 5, no. 1 (March 1, 2017): 43–49. http://dx.doi.org/10.1515/acb-2017-0004.
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Summary Cell death plays an important role in maintaining the homeostasis of multicellular organisms. It can occur in a controlled manner by apoptosis or autophagy. Cell death which occurs regardless of regulatory factors include necrosis, mitotic catastrophe or oncosis. Apoptosis and necrosis are cellular process that leads to cell death. However their mechanisms are different, although factors triggering them can be similar. Necrosis and apoptosis have many different characteristics in terms of biochemistry and morphology. There are two main pathways of apoptosis induction signal: receptor - dependent and mitochondrial. The outsider apoptotic pathway is induced by external factors stimulating membrane receptors having an intracellular domain called death domain. Mitochondrial apoptotic pathway is activated by increased concentration of reactive oxygen species (ROS), DNA damage, disorders electrolyte transport and an increase in the concentration of the calcium ions in the cytoplasm. In response to stress-factors, mitochondrial channels are opened, so that is released into the cytoplasm cytochrome C. This work is aimed at an overall description of exchanged processes.
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Hess, S., and H. Engelmann. "A novel function of CD40: induction of cell death in transformed cells." Journal of Experimental Medicine 183, no. 1 (January 1, 1996): 159–67. http://dx.doi.org/10.1084/jem.183.1.159.
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CD40 is known as an important T-B cell interaction molecule which rescues B lymphocytes from undergoing apoptosis. Like other receptors of the tumor necrosis factor (TNF) receptor gene family, CD40 is expressed on cells of different tissue origins including some transformed cells. In contrast to its well-studied effects on B cells, the biological functions of CD40 in non-immune cells remain largely unknown. Here we show that CD40 ligation induces apoptotic cell death in transformed cells of mesenchymal and epithelial origin. This CD40-mediated cell death seems to use a preformed signaling pathway since it occurs even when protein synthesis is blocked. Notably, the CD40 cytoplasmic domain shares a structural homology with the recently defined "death domains" of the 55-kD TNF receptor (p55TNFR) and Fas. Despite these structural similarities, differences are seen in the way phorbol myristate acetate, interleukin 1, TNF, and various metabolic inhibitors influence the cellular responsiveness to CD40, p55TNFR, and Fas-mediated killing. Our study indicates that CD40 induces cell death by a distinct mechanism.
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Rossin, Aurélie, Mathieu Derouet, Fadi Abdel-Sater, and Anne-Odile Hueber. "Palmitoylation of the TRAIL receptor DR4 confers an efficient TRAIL-induced cell death signalling." Biochemical Journal 419, no. 1 (March 13, 2009): 185–94. http://dx.doi.org/10.1042/bj20081212.
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S-palmitoylation is a lipid modification that regulates membrane–protein association and influences protein trafficking, stability or aggregation, thus playing an important role in protein signalling. We previously demonstrated that the palmitoylation of Fas, one of the DD (death domain)-containing members of the TNFR [TNF (tumour necrosis factor) receptor] superfamily, is essential for the redistribution of this receptor into lipid rafts, an obligatory step for the death signal transmission. Here we investigate the requirement of protein palmitoylation in the activities of other DD-containing death receptors. We show that DR4 is palmitoylated, whereas DR5 and TNFR1 are not. Furthermore, DR4 palmitoylation is required for its raft localization and its ability to oligomerize, two essential features in TRAIL (TNF-related apoptosis-inducing ligand)-induced death signal transmission.
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Pettersen, Rolf D., Kjetil Hestdal, Mette Kløvstad Olafsen, Sverre O. Lie, and Frederik P. Lindberg. "CD47 Signals T Cell Death." Journal of Immunology 162, no. 12 (June 15, 1999): 7031–40. http://dx.doi.org/10.4049/jimmunol.162.12.7031.
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Abstract Activation-induced death of T cells regulates immune responses and is considered to involve apoptosis induced by ligation of Fas and TNF receptors. The role of other receptors in signaling T cell death is less clear. In this study we demonstrate that activation of specific epitopes on the Ig variable domain of CD47 rapidly induces apoptosis of T cells. A new mAb, Ad22, to this site induces apoptosis of Jurkat cells and CD3ε-stimulated PBMC, as determined by morphological changes, phosphatidylserine exposure on the cell surface, uptake of propidium iodide, and true counts by flow cytometry. In contrast, apoptosis was not observed following culture with anti-CD47 mAbs 2D3 or B6H12 directed to a distant or closely adjacent region, respectively. CD47-mediated cell death was independent of CD3, CD4, CD45, or p56lck involvement as demonstrated by studies with variant Jurkat cell lines deficient in these signaling pathways. However, coligation of CD3ε and CD47 enhanced phosphatidylserine externalization on Jurkat cells with functional CD3. Furthermore, normal T cells required preactivation to respond with CD47-induced apoptosis. CD47-mediated cell death appeared to proceed independent of Fas or TNF receptor signaling and did not involve characteristic DNA fragmentation or requirement for IL-1β-converting enzyme-like proteases or CPP32. Taken together, our data demonstrate that under appropriate conditions, CD47 activation results in very rapid T cell death, apparently mediated by a novel apoptotic pathway. Thus, CD47 may be critically involved in controlling the fate of activated T cells.
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Knox, Pauline G., Clare C. Davies, Marina Ioannou, and Aristides G. Eliopoulos. "The death domain kinase RIP1 links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas." Journal of Cell Biology 192, no. 3 (January 31, 2011): 391–99. http://dx.doi.org/10.1083/jcb.201003087.
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CD40, a tumor necrosis factor (TNF) receptor family member, is widely recognized for its prominent role in the antitumor immune response. The immunostimulatory effects of CD40 ligation on malignant cells can be switched to apoptosis upon disruption of survival signals transduced by the binding of the adaptor protein TRAF6 to CD40. Apoptosis induction requires a TRAF2-interacting CD40 motif but is initiated within a cytosolic death-inducing signaling complex after mobilization of receptor-bound TRAF2 to the cytoplasm. We demonstrate that receptor-interacting protein 1 (RIP1) is an integral component of this complex and is required for CD40 ligand-induced caspase-8 activation and tumor cell killing. Degradation of the RIP1 K63 ubiquitin ligases cIAP1/2 amplifies the CD40-mediated cytotoxic effect, whereas inhibition of CYLD, a RIP1 K63 deubiquitinating enzyme, reduces it. This two-step mechanism of apoptosis induction expands our appreciation of commonalities in apoptosis regulatory pathways across the TNF receptor superfamily and provides a telling example of how TNF family receptors usurp alternative programs to fulfill distinct cellular functions.
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Clarke, Penny, Suzanne M. Meintzer, Spencer Gibson, Christian Widmann, Timothy P. Garrington, Gary L. Johnson, and Kenneth L. Tyler. "Reovirus-Induced Apoptosis Is Mediated by TRAIL." Journal of Virology 74, no. 17 (September 1, 2000): 8135–39. http://dx.doi.org/10.1128/jvi.74.17.8135-8139.2000.
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ABSTRACT Members of the tumor necrosis factor (TNF) receptor superfamily and their activating ligands transmit apoptotic signals in a variety of systems. We now show that the binding of TNF-related, apoptosis-inducing ligand (TRAIL) to its cellular receptors DR5 (TRAILR2) and DR4 (TRAILR1) mediates reovirus-induced apoptosis. Anti-TRAIL antibody and soluble TRAIL receptors block reovirus-induced apoptosis by preventing TRAIL-receptor binding. In addition, reovirus induces both TRAIL release and an increase in the expression of DR5 and DR4 in infected cells. Reovirus-induced apoptosis is also blocked following inhibition of the death receptor-associated, apoptosis-inducing molecules FADD (for FAS-associated death domain) and caspase 8. We propose that reovirus infection promotes apoptosis via the expression of DR5 and the release of TRAIL from infected cells. Virus-induced regulation of the TRAIL apoptotic pathway defines a novel mechanism for virus-induced apoptosis.
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Zhang, Haibing, and Jianke Zhang. "Novel functions of cFLIP in lymphocyte death signaling (163.22)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 163.22. http://dx.doi.org/10.4049/jimmunol.188.supp.163.22.
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Abstract Fas/Apo-1 signals through the FADD (Fas-associated death domain) adaptor protein, which recruits and activates the apical caspase 8 and leads to apoptosis. cFLIP is a homologue of caspase 8 but lacks caspase activities, and presumably inhibits apoptosis induced by the death receptors by competing with caspase 8 for binding to FADD. FADD, Caspase 8, and cFLIP form a signaling complex during death receptor-induced apoptosis. In addition to the cell death function, deletion of FADD, Caspase 8, and cFLIP results in embryonic lethality and lymphocytes proliferation defects upon TCR-induced or Toll-like receptor stimulation. Previous studies have shown that death receptors also induce a particular type of necrotic death in certain cell types, termed necroptosis, which is dependent on RIP1 and RIP3. Recently, our group and other groups showed that RIP1 or RIP3 deficiency could rescue the embryonic lethality and T cell proliferation defects caused by FADD or Caspase 8 deficiency. These studies identified a critical function of FADD and caspase-8 in vivo in suppressing RIP1/RIP3-dependent necrosis that is essential for embryonic development and T cell proliferation. Using a conditional cFLIP knockout mouse model and various in vitro systems, our recent studies reveal novel functions for cFLIP in regulating apoptosis and necrosis in lymphocytes.
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Mérino, Delphine, Najoua Lalaoui, Alexandre Morizot, Pascal Schneider, Eric Solary, and Olivier Micheau. "Differential Inhibition of TRAIL-Mediated DR5-DISC Formation by Decoy Receptors 1 and 2." Molecular and Cellular Biology 26, no. 19 (October 1, 2006): 7046–55. http://dx.doi.org/10.1128/mcb.00520-06.
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ABSTRACT Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that induces cancer cell death by apoptosis with some selectivity. TRAIL-induced apoptosis is mediated by the transmembrane receptors death receptor 4 (DR4) (also known as TRAIL-R1) and DR5 (TRAIL-R2). TRAIL can also bind decoy receptor 1 (DcR1) (TRAIL-R3) and DcR2 (TRAIL-R4) that fail to induce apoptosis since they lack and have a truncated cytoplasmic death domain, respectively. In addition, DcR1 and DcR2 inhibit DR4- and DR5-mediated, TRAIL-induced apoptosis and we demonstrate here that this occurs through distinct mechanisms. While DcR1 prevents the assembly of the death-inducing signaling complex (DISC) by titrating TRAIL within lipid rafts, DcR2 is corecruited with DR5 within the DISC, where it inhibits initiator caspase activation. In addition, DcR2 prevents DR4 recruitment within the DR5 DISC. The specificity of DcR1- and DcR2-mediated TRAIL inhibition reveals an additional level of complexity for the regulation of TRAIL signaling.
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Young, Jennifer, Tina He, Boris Reizis, and Astar Winoto. "Consequences of dendritic cell necroptosis on the immune system (P5105)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 129.17. http://dx.doi.org/10.4049/jimmunol.190.supp.129.17.
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Abstract Dendritic cells (DCs) are essential in eliciting protective responses against pathogens, thus appropriate DC functions are essential in maintaining proper immune responses. The maintenance of DC homeostasis relies heavily on apoptosis to prevent disease development, and inhibition of DC apoptosis has been previously reported to induce systemic autoimmune disease. Fas-associated death domain-containing protein (FADD) is a critical adaptor protein that interacts with caspase-8 to transmit apoptotic signals downstream of the tumor necrosis factor family of death receptors. More recently, an alternative form of cell death, termed necroptosis, was reported to be downstream of the death receptors. Necroptosis is caspase-independent and requires the kinase activities of receptor interacting serine/threonine protein kinase 1 (RIP1) and RIP3. To investigate the role of FADD in DC death, DC-specific FADD conditional knockout mice were generated. Interestingly, these mice developed an inflammatory phenotype. We further elucidated the cause of inflammation by crossing the mice to RIP3-/-, MyD88-/- and MyD88flox/flox mutant mice. Our recent findings based on the analysis of these mice will be discussed.
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Bao, Jianxin, Deon Wolpowitz, Lorna W. Role, and David A. Talmage. "Back signaling by the Nrg-1 intracellular domain." Journal of Cell Biology 161, no. 6 (June 23, 2003): 1133–41. http://dx.doi.org/10.1083/jcb.200212085.
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Transmembrane isoforms of neuregulin-1 (Nrg-1), ligands for erbB receptors, include an extracellular domain with an EGF-like sequence and a highly conserved intracellular domain (ICD) of unknown function. In this paper, we demonstrate that transmembrane isoforms of Nrg-1 are bidirectional signaling molecules in neurons. The stimuli for Nrg-1 back signaling include binding of erbB receptor dimers to the extracellular domain of Nrg-1 and neuronal depolarization. These stimuli elicit proteolytic release and translocation of the ICD of Nrg-1 to the nucleus. Once in the nucleus, the Nrg-1 ICD represses expression of several regulators of apoptosis, resulting in decreased neuronal cell death in vitro. Thus, regulated proteolytic processing of Nrg-1 results in retrograde signaling that appears to mediate contact and activity-dependent survival of Nrg-1–expressing neurons.
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Gnesutta, Nerina, and Audrey Minden. "Death Receptor-Induced Activation of Initiator Caspase 8 Is Antagonized by Serine/Threonine Kinase PAK4." Molecular and Cellular Biology 23, no. 21 (November 1, 2003): 7838–48. http://dx.doi.org/10.1128/mcb.23.21.7838-7848.2003.
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ABSTRACT Normal cell growth requires a precisely controlled balance between cell death and survival. This involves activation of different types of intracellular signaling cascades within the cell. While some types of signaling proteins regulate apoptosis, or programmed cell death, other proteins within the cell can promote survival. The serine/threonine kinase PAK4 can protect cells from apoptosis in response to several different types of stimuli. As is the case for other members of the p21-activated kinase (PAK) family, one way that PAK4 may promote cell survival is by phosphorylating and thereby inhibiting the proapoptotic protein Bad. This leads in turn to the inhibition of effector caspases such as caspase 3. Here we show that in response to cytokines which activate death domain-containing receptors, such as the tumor necrosis factor and Fas receptors, PAK4 can inhibit the death signal by a different mechanism. Under these conditions, PAK4 inhibits apoptosis early in the caspase cascade, antagonizing the activation of initiator caspase 8. This inhibition, which does not require PAK4's kinase activity, may involve inhibition of caspase 8 recruitment to the death domain receptors. This role in regulating initiator caspases is an entirely novel role for the PAK proteins and suggests a new mechanism by which these proteins promote cell survival.
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Cesari, Stella, John Moore, Chunhong Chen, Daryl Webb, Sambasivam Periyannan, Rohit Mago, Maud Bernoux, Evans S. Lagudah, and Peter N. Dodds. "Cytosolic activation of cell death and stem rust resistance by cereal MLA-family CC–NLR proteins." Proceedings of the National Academy of Sciences 113, no. 36 (August 23, 2016): 10204–9. http://dx.doi.org/10.1073/pnas.1605483113.
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Plants possess intracellular immune receptors designated “nucleotide-binding domain and leucine-rich repeat” (NLR) proteins that translate pathogen-specific recognition into disease-resistance signaling. The wheat immune receptors Sr33 and Sr50 belong to the class of coiled-coil (CC) NLRs. They confer resistance against a broad spectrum of field isolates of Puccinia graminis f. sp. tritici, including the Ug99 lineage, and are homologs of the barley powdery mildew-resistance protein MLA10. Here, we show that, similarly to MLA10, the Sr33 and Sr50 CC domains are sufficient to induce cell death in Nicotiana benthamiana. Autoactive CC domains and full-length Sr33 and Sr50 proteins self-associate in planta. In contrast, truncated CC domains equivalent in size to an MLA10 fragment for which a crystal structure was previously determined fail to induce cell death and do not self-associate. Mutations in the truncated region also abolish self-association and cell-death signaling. Analysis of Sr33 and Sr50 CC domains fused to YFP and either nuclear localization or nuclear export signals in N. benthamiana showed that cell-death induction occurs in the cytosol. In stable transgenic wheat plants, full-length Sr33 proteins targeted to the cytosol provided rust resistance, whereas nuclear-targeted Sr33 was not functional. These data are consistent with CC-mediated induction of both cell-death signaling and stem rust resistance in the cytosolic compartment, whereas previous research had suggested that MLA10-mediated cell-death and disease resistance signaling occur independently, in the cytosol and nucleus, respectively.
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Kourelis, Jiorgos, Mauricio P. Contreras, Adeline Harant, Hsuan Pai, Daniel Lüdke, Hiroaki Adachi, Lida Derevnina, Chih-Hang Wu, and Sophien Kamoun. "The helper NLR immune protein NRC3 mediates the hypersensitive cell death caused by the cell-surface receptor Cf-4." PLOS Genetics 18, no. 9 (September 22, 2022): e1010414. http://dx.doi.org/10.1371/journal.pgen.1010414.
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Cell surface pattern recognition receptors (PRRs) activate immune responses that can include the hypersensitive cell death. However, the pathways that link PRRs to the cell death response are poorly understood. Here, we show that the cell surface receptor-like protein Cf-4 requires the intracellular nucleotide-binding domain leucine-rich repeat containing receptor (NLR) NRC3 to trigger a confluent cell death response upon detection of the fungal effector Avr4 in leaves of Nicotiana benthamiana. This NRC3 activity requires an intact N-terminal MADA motif, a conserved signature of coiled-coil (CC)-type plant NLRs that is required for resistosome-mediated immune responses. A chimeric protein with the N-terminal α1 helix of Arabidopsis ZAR1 swapped into NRC3 retains the capacity to mediate Cf-4 hypersensitive cell death. Pathogen effectors acting as suppressors of NRC3 can suppress Cf-4-triggered hypersensitive cell-death. Our findings link the NLR resistosome model to the hypersensitive cell death caused by a cell surface PRR.
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Vandenabeele, P. "More than one way to die: apoptosis and necrosis induced by death domain receptors." European Journal of Cancer 37 (April 2001): S7. http://dx.doi.org/10.1016/s0959-8049(01)80512-8.
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McCarthy, Aonghus J., Caroline Coleman-Vaughan, and Justin V. McCarthy. "Regulated intramembrane proteolysis: emergent role in cell signalling pathways." Biochemical Society Transactions 45, no. 6 (October 27, 2017): 1185–202. http://dx.doi.org/10.1042/bst20170002.
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Receptor signalling events including those initiated following activation of cytokine and growth factor receptors and the well-characterised death receptors (tumour necrosis factor receptor, type 1, FasR and TRAIL-R1/2) are initiated at the cell surface through the recruitment and formation of intracellular multiprotein signalling complexes that activate divergent signalling pathways. Over the past decade, research studies reveal that many of these receptor-initiated signalling events involve the sequential proteolysis of specific receptors by membrane-bound proteases and the γ-secretase protease complexes. Proteolysis enables the liberation of soluble receptor ectodomains and the generation of intracellular receptor cytoplasmic domain fragments. The combined and sequential enzymatic activity has been defined as regulated intramembrane proteolysis and is now a fundamental signal transduction process involved in the termination or propagation of receptor signalling events. In this review, we discuss emerging evidence for a role of the γ-secretase protease complexes and regulated intramembrane proteolysis in cell- and immune-signalling pathways.
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Burns, Kimberly, Sophie Janssens, Brian Brissoni, Natalia Olivos, Rudi Beyaert, and Jürg Tschopp. "Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4." Journal of Experimental Medicine 197, no. 2 (January 13, 2003): 263–68. http://dx.doi.org/10.1084/jem.20021790.
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Toll-like receptors (TLRs) and members of the proinflammatory interleukin 1 receptor (IL-1R) family are dependent on the presence of MyD88 for efficient signal transduction. The bipartite nature of MyD88 (N-terminal death domain [DD] and COOH-terminal Toll/IL-1 receptor [TIR] domain) allows it to link the TIR domain of IL-1R/TLR with the DD of the Ser/Thr kinase termed IL-1R–associated kinase (IRAK)-1. This triggers IRAK-1 phosphorylation and in turn the activation of multiple signaling cascades such as activation of the transcription factor nuclear factor (NF)-κB. In contrast, expression of MyD88 short (MyD88s), an alternatively spliced form of MyD88 that lacks only the short intermediate domain separating the DD and TIR domains, leads to a shutdown of IL-1/lipopolysaccharide-induced NF-κB activation. Here, we provide the molecular explanation for this difference. MyD88 but not MyD88s strongly interacts with IRAK-4, a newly identified kinase essential for IL-1R/TLR signaling. In the presence of MyD88s, IRAK-1 is not phosphorylated and neither activates NF-κB nor is ubiquitinated. Thus, MyD88s acts as a negative regulator of IL-1R/TLR/MyD88-triggered signals, leading to a transcriptionally controlled negative regulation of innate immune responses.
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Kataoka, Takao, Michael Schröter, Michael Hahne, Pascal Schneider, Martin Irmler, Margot Thome, Cristopher J. Froelich, and Jürg Tschopp. "FLIP Prevents Apoptosis Induced by Death Receptors But Not by Perforin/Granzyme B, Chemotherapeutic Drugs, and Gamma Irradiation." Journal of Immunology 161, no. 8 (October 15, 1998): 3936–42. http://dx.doi.org/10.4049/jimmunol.161.8.3936.
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Abstract FLICE-inhibitory protein, FLIP (Casper/I-FLICE/FLAME-1/CASH/CLARP/MRIT), which contains two death effector domains and an inactive caspase domain, binds to FADD and caspase-8, and thereby inhibits death receptor-mediated apoptosis. Here, we characterize the inhibitory effect of FLIP on a variety of apoptotic pathways. Human Jurkat T cells undergoing Fas ligand-mediated apoptosis in response to CD3 activation were completely resistant when transfected with FLIP. In contrast, the presence of FLIP did not affect apoptosis induced by granzyme B in combination with adenovirus or perforin. Moreover, the Fas ligand, but not the perforin/granzyme B-dependent lytic pathway of CTL, was inhibited by FLIP. Apoptosis mediated by chemotherapeutic drugs (i.e., doxorubicin, etoposide, and vincristine) and gamma irradiation was not affected by FLIP or the absence of Fas, indicating that these treatments can induce cell death in a Fas-independent and FLIP-insensitive manner.
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Kim, Tae Kang, and Myung-Shik Lee. "Innate immune receptors in type 1 diabetes: the relationship to cell death-associated inflammation." Biochemical Society Transactions 48, no. 3 (June 8, 2020): 1213–25. http://dx.doi.org/10.1042/bst20200131.
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The importance of innate immunity in host defense and inflammatory responses has been clearly demonstrated after the discovery of innate immune receptors such as Toll-like receptors (TLRs) or Nucleotide-binding oligomerization domain-containing protein (Nod)-like receptors (NLRs). Innate immunity also plays a critical role in diverse pathological conditions including autoimmune diseases such as type 1 diabetes (T1D). In particular, the role of a variety of innate immune receptors in T1D has been demonstrated using mice with targeted disruption of such innate immune receptors. Here, we discuss recent findings showing the role of innate immunity in T1D that were obtained mostly from studies of genetic mouse models of innate immune receptors. In addition, the role of innate immune receptors involved in the pathogenesis of T1D in sensing death-associated molecular patterns (DAMPs) released from dead cells or pathogen-associated molecular patterns (PAMPs) will also be covered. Elucidation of the role of innate immune receptors in T1D and the nature of DAMPs sensed by such receptors may lead to the development of new therapeutic modalities against T1D.
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Saumet, Anne, Mouna Ben Slimane, Michel Lanotte, Jack Lawler, and Véronique Dubernard. "Type 3 repeat/C-terminal domain of thrombospondin-1 triggers caspase-independent cell death through CD47/αvβ3 in promyelocytic leukemia NB4 cells." Blood 106, no. 2 (July 15, 2005): 658–67. http://dx.doi.org/10.1182/blood-2004-09-3585.
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Abstract By means of its antiangiogenic activity, thrombospondin-1 (TSP-1) exerts indirect antitumoral action on solid tumors. Here, we investigated potential antitumor action in an in vitro cell model for promyelocytic leukemia (NB4-LR1), resistant to retinoid maturation. Purified soluble TSP-1 added to cultures induced a strong dose-dependent growth inhibition and a slowly developing maturation-independent cell death. Recombinant fragments of TSP-1 allowed mapping of these activities to its type 3 repeat/C-terminal domain, features that are distinct from those of TSP-1 action on solid tumors, previously ascribed to the type 1 repeat domain. Cell death in leukemia was characterized as a caspase-independent mechanism, without DNA fragmentation, but phosphatidylserine externalization followed by membrane permeabilization. Mitochondria membrane depolarization was inherent to TSP-1 action but did not produce release of death-promoting proteins (eg, noncaspase apoptosis regulators, apoptosis-induced factor [AIF], endonuclease G, or Omi/HtrA2 or the caspase regulators, cytochrome c or second mitochondrial activator of caspase/direct inhibitor of apoptosis protein-binding protein with low isoelectric point [Smac/DIABLO]). Although detected, reactive oxygen species (ROS) production was likely not involved in the death process. Finally, receptor agonist RFYVVM and RGD peptides indicated that TSP-1 death effects are mediated by membrane receptors CD47 and αvβ3. These results demonstrated a new domain-specific antitumoral activity of TSP-1 on a leukemia cell line, which extends TSP-1 therapeutic potential outside the area of vascularized solid tumors. (Blood. 2005;106:658-667)
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Lapin, Dmitry, Viera Kovacova, Xinhua Sun, Joram A. Dongus, Deepak Bhandari, Patrick von Born, Jaqueline Bautor, et al. "A Coevolved EDS1-SAG101-NRG1 Module Mediates Cell Death Signaling by TIR-Domain Immune Receptors." Plant Cell 31, no. 10 (July 16, 2019): 2430–55. http://dx.doi.org/10.1105/tpc.19.00118.
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