Academic literature on the topic 'HtrA2/Omi'
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Journal articles on the topic "HtrA2/Omi"
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Su, Xiao Juan, Lingyi Huang, Yi Qu, and Dezhi Mu. "Progress in research on the role of Omi/HtrA2 in neurological diseases." Reviews in the Neurosciences 30, no. 3 (April 24, 2019): 279–87. http://dx.doi.org/10.1515/revneuro-2018-0004.
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Abstract Omi/HtrA2 is a serine protease present in the mitochondrial space. When stimulated by external signals, HtrA2 is released into the mitochondrial matrix where it regulates cell death through its interaction with apoptotic and autophagic signaling pathways. Omi/HtrA2 is closely related to the pathogenesis of neurological diseases, such as neurodegeneration and hypoxic ischemic brain damage. Here, we summarize the biological characteristics of Omi/HtrA2 and its role in neurological diseases, which will provide new hints in developing Omi/HtrA2 as a therapeutic target for neurological diseases.
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Gupta, Sanjeev, Rajesh Singh, Pinaki Datta, ZhiJia Zhang, Christopher Orr, Zhixian Lu, Garrett DuBois, et al. "The C-terminal Tail of Presenilin Regulates Omi/HtrA2 Protease Activity." Journal of Biological Chemistry 279, no. 44 (August 4, 2004): 45844–54. http://dx.doi.org/10.1074/jbc.m404940200.
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Presenilin mutations are responsible for most cases of autosomal dominant inherited forms of early onset Alzheimer disease. Presenilins play an important role in amyloid β-precursor processing, NOTCH receptor signaling, and apoptosis. However, the molecular mechanisms by which presenilins regulate apoptosis are not fully understood. Here, we report that presenilin-1 (PS1) regulates the proteolytic activity of the serine protease Omi/HtrA2 through direct interaction with its regulatory PDZ domain. We show that a peptide corresponding to the cytoplasmic C-terminal tail of PS1 dramatically increases the proteolytic activity of Omi/HtrA2 toward the inhibitor of apoptosis proteins and β-casein and induces cell death in an Omi/HtrA2-dependent manner. Consistent with these results, ectopic expression of full-length PS1, but not PS1 lacking the C-terminal PDZ binding motif, potentiated Omi/HtrA2-induced cell death. Our results suggest that the C terminus of PS1 is an activation peptide ligand for the PDZ domain of Omi/HtrA2 and may regulate the protease activity of Omi/HtrA2 after its release from the mitochondria during apoptosis. This mechanism of Omi/HtrA2 activation is similar to the mechanism of activation of the related bacterial DegS protease by the outer-membrane porins.
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Hur, Kang, Kim, Lee, Kim, Nam, Rhim, and Yoon. "Serine Protease HtrA2/Omi Deficiency Impairs Mitochondrial Homeostasis and Promotes Hepatic Fibrogenesis via Activation of Hepatic Stellate Cells." Cells 8, no. 10 (September 20, 2019): 1119. http://dx.doi.org/10.3390/cells8101119.
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The loss of mitochondrial function impairs intracellular energy production and potentially results in chronic liver disease. Increasing evidence suggests that mitochondrial dysfunction in hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thereby resulting in hepatic fibrogenesis. High-temperature requirement protein A2 (HtrA2/Omi), a mitochondrial serine protease with various functions, is responsible for quality control in mitochondrial homeostasis. However, little information is available regarding its role in mitochondrial damage during the development of liver fibrosis. This study examined whether HtrA2/Omi regulates mitochondrial homeostasis in hepatocyte during the development of hepatic fibrogenesis. In this study, we demonstrated that HtrA2/Omi expression considerably decreased in liver tissues from the CCl4-induced liver fibrotic mice model and from patients with liver cirrhosis. Knockdown of HtrA2/Omi in hepatocytes induced the accumulation of damaged mitochondria and provoked mitochondrial reactive oxygen species (mtROS) stress. We further show that the damaged mtDNA isolated from HtrA2/Omi-deficient hepatocytes as a form of damage-associated molecular patterns can induce HSCs activation. Moreover, we found that motor neuron degeneration 2-mutant mice harboring the missense mutation Ser276Cys in the protease domain of HtrA2/Omi displayed altered mitochondrial morphology and function, which increased oxidative stress and promoted liver fibrosis. Conversely, the overexpression of HtrA2/Omi via hydrodynamics-based gene transfer led to the antifibrotic effects in CCl4-induced liver fibrosis mice model through decreasing collagen accumulation and enhancing anti-oxidative activity by modulating mitochondrial homeostasis in the liver. These results suggest that suppressing HtrA2/Omi expression promotes hepatic fibrogenesis via modulating mtROS generation, and these novel mechanistic insights involving the regulation of mitochondrial homeostasis by HtrA2/Omi may be of importance for developing new therapeutic strategies for hepatic fibrosis.
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Wang, Pengfei, Yueyu Hu, Danhua Yao, and Yousheng Li. "Omi/HtrA2 Regulates a Mitochondria-Dependent Apoptotic Pathway in a Murine Model of Septic Encephalopathy." Cellular Physiology and Biochemistry 49, no. 6 (2018): 2163–73. http://dx.doi.org/10.1159/000493819.
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Background/Aims: the pathogenesis of sepsis-associated encephalopathy (SAE) is multifactorial, involving neurotransmitter alterations, inflammatory cytokines, oxidative damage, mitochondrial dysfunction, apoptosis, and other factors. Mitochondria are major producers of reactive oxygen species, resulting in cellular injury. Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent cell death; it is translocated from mitochondria to the cytosol after an apoptotic insult. We previously found that UCF-101, a specific inhibitor of Omi/HtrA2, has neuroprotective effects on cerebral oxidative injury and cognitive impairment in septic rats. In this study, the mechanisms and molecular pathways underlying these effects were investigated. Methods: Male Sprague–Dawley rats were subjected to cecal ligation and puncture (CLP) or sham-operated laparotomy and were administered vehicle or UCF-101 (10 µmol/kg). The hippocampus was isolated for subsequent analysis. Omi/HtrA2 expression in the mitochondria or cytosol was evaluated by immunofluorescence or western blotting. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was utilized to evaluate levels of apoptosis, and western blotting was used to evaluate apoptosis-related proteins, such as cleaved caspase-3, caspase-9, and poly (ADP-ribose) polymerase (PARP). Tight junction expression was assessed by immunofluorescence and western blotting. Mitochondrial function, inflammatory cytokines, and oxidative stress were also assayed. In addition, a wet/dry method was used to evaluate brain edema and Evans blue extravasation was used to evaluate blood–brain barrier (BBB) integrity. Results: After CLP treatment, the hippocampus exhibited a mild increase in Omi/HtrA2 expression; cytosolic Omi/HtrA2 expression increased significantly, whereas mitochondrial Omi/HtrA2 expression was reduced, indicating that CLP-induced oxidative stress resulted in the translocation of Omi/HtrA2 from mitochondria to the cytosol. Hippocampal cleaved caspase-3, caspase-9, and PARP levels were significantly higher in animals treated with CLP than in sham-operated animals, while XIAP expression was lower. Treatment with UCF-101 prevented the mobilization of Omi/HtrA2 from mitochondria to the cytosol, attenuated XIAP degradation, and decreased cleaved caspase-3, caspase-9, and PARP expression as well as apoptosis. UCF-101 also reversed the decreased mitochondrial complex I, II, and III respiration and the reduced ATP caused by CLP. In addition, UCF-101 treatment resulted in a significant improvement in BBB integrity, as demonstrated by increased occludin, claudin-5, and zonula occludens 1 levels and reduced Evans blue extravasation. No significant effects of UCF-101 on brain edema were found. Inflammatory cytokines and oxidative stress were significantly higher in the CLP-treated group than in the sham-operated group. However, the inhibition of Omi/HtrA2 by UCF-101 significantly alleviated these responses. Conclusion: Our data indicated that Omi/ HtrA2 regulates a mitochondria-dependent apoptotic pathway in a murine model of septic encephalopathy. Inhibition of Omi/HtrA2 by UCF-101 leads to neuroprotection by inhibiting the cytosolic translocation of Omi/HtrA2 and antagonizing the caspase-dependent apoptosis pathway. Therapeutic interventions that inhibit Omi/HtrA2 translocation or protease activity may provide a novel method to treat SAE.
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Li, Shaoying, Mei Wan, Xu Cao, and Yongsheng Ren. "Expression of AIF and HtrA2/Omi in Small Lymphocytic Lymphoma and Diffuse Large B-Cell Lymphoma." Archives of Pathology & Laboratory Medicine 135, no. 7 (July 1, 2011): 903–8. http://dx.doi.org/10.5858/2010-0003-oar1.1.
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Abstract Context.—The pathogenesis of non-Hodgkin lymphoma may involve deregulation of apoptosis. In response to apoptotic stimuli, several proapoptotic proteins are released into the cytoplasm from the mitochondria, including second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein binding protein with low pI (Smac/DIABLO), apoptosis-inducing factor (AIF), and high temperature requirement protein A2 (HtrA2/Omi). Apoptosis-inducing factor promotes apoptosis through a caspase-independent pathway, while Smac/DIABLO and HtrA2/Omi do so through both caspase-dependent and caspase-independent pathways. Smac/DIABLO was reported to be strongly positive in diffuse large B-cell lymphoma (DLBCL) and virtually absent in small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). Little is known about the expression of AIF and HtrA2/Omi in lymphomas. Objective.—To evaluate the expression of AIF and HtrA2/Omi in SLL and DLBCL. Design.—Twenty-three DLBCLs, 20 SLLs/CLLs, and 10 benign lymph nodes were evaluated for AIF and HtrA2/Omi expression by immunohistochemical staining. Results.—Apoptosis-inducing factor was strongly and diffusely expressed in 19 of 23 (83%) cases of DLBCL with comparable expression pattern between germinal center–like and non-germinal center–like subgroups. Apoptosis-inducing factor was weakly positive in 15 of 20 (75%) cases of SLL/CLL with increased intensity in pseudofollicles. In contrast, HtrA2/Omi was weakly expressed in SLL/CLL (17 of 20; 85%) and DLBCL (18 of 23; 78%). Conclusions.—The different expression level and pattern of AIF and HtrA2/Omi in SLL/CLL and DLBCL may suggest different apoptotic mechanisms involved in the pathogenesis and prognosis of these diseases. HtrA2/Omi does not appear to be a major player in the regulation of apoptosis of DLBCL and SLL/CLL.
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Winkler, Jeannine, Margaret Rand, Markus Schmugge, and Oliver Speer. "Omi/HtrA2 and XIAP are components of platelet apoptosis signalling." Thrombosis and Haemostasis 109, no. 03 (2013): 532–39. http://dx.doi.org/10.1160/th12-06-0404.
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SummaryAlthough platelets possess the hallmarks of apoptosis such as activation of caspases, cytochrome c release and depolarisation of the mitochondrial transmembrane potential (ΔΨm), their entire apoptotic-signalling pathway is not totally understood. Therefore we studied the expression of various apoptotic proteins and found that platelets contain the pro-apoptotic proteins Omi/HtrA2 and Smac/Diablo, as well as their target the X-linked inhibitor of apoptosis XIAP. Omi/HtrA2 and Smac/Diablo were released from mitochondria into the platelet cytosol together with cytochrome c after induction of apoptosis by the Ca2+ ionophore A23187 or the BH3 mimetic ABT-737, and to a lesser extent, after platelet stimulation with collagen and thrombin. Inhibition of Omi/HtrA2 led to decreased levels of activated caspase-3/7 and caspase-9, but did not abolish loss of ΔΨm or prevent release of Omi/HtrA2 from mitochondria. These results indicate that platelets have a functional intrinsic apoptotic-signalling pathway including the pro-apoptotic protease Omi/HtrA2 and its target protein XIAP.
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Senn, Joseph, Vilmos Csizmadia, Paul Hales, Larry Dick, and Vivek J. Kadambi. "Proteasome Inhibitors Do Not Inhibit the Serine Protease HtrA2/Omi." Blood 120, no. 21 (November 16, 2012): 5023. http://dx.doi.org/10.1182/blood.v120.21.5023.5023.
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Abstract Abstract 5023 Based on unprecedented efficacy, the proteasome inhibitor (PI) bortezomib has become the cornerstone of multiple myeloma treatment. Nevertheless, in a subset of patients bortezomib causes painful peripheral neuropathy and this side effect can limit its potential benefit for those patients. Although the mechanism of bortezomib associated neuropathy is unknown, we have previously suggested that it is related to the mechanism of action (Csizmadia at. al. Vet Pathol 2010; 47:358–367.). Recently Arastu-Kapur et al. (Clin Cancer Res 2011;17:2734–2743.) have reported that the serine protease HtrA2/Omi was inhibited by bortezomib (a peptide boronate proteasome inhibitor) and not by carfilzomib (an epoxyketone proteasome inhibitor). Further, since HtrA2/Omi is involved in neuronal survival (Martins et al. Mol Cell Biol 2004; 24: 9848–9862.) they suggested that this off target inhibition by bortezomib could be the mechanism underlying bortezomib associated peripheral neuropathy. To confirm and extend these published results, we investigated the effects of these two PIs on HtrA2/Omi activity in recombinant enzyme assays, in SH-SY5Y neuroblastoma-, and wild type and HtrA2/Omi double negative mouse embryonic fibroblast cells (MEF). In contrast to the results of Arastu-Kapur et al., our results clearly demonstrated that neither bortezomib nor carfilzomib inhibits HtrA2/Omi in recombinant enzyme assays at concentrations up to 100μM. As a positive control we used Ucf-101 an HtrA2/Omi specific inhibitor (Cilenti et al. J Biol Chem 2003; 278:11489–11494.) which in our assay behaved in a manner consistent with the published literature. Similarly, in MEF cells, only Ucf-101 prevented the degradation of validated HtrA2/Omi substrates eIF4G1 and UCH-L1, while neither bortezomib nor carfilzomib prevented the degradation of these two substrates. In conclusion, we have assessed the protease activity of HtrA2/Omi both in vitro with purified enzyme and in cultured cells and we find that neither PI inhibits this protease. Therefore we think it is unlikely that PI associated peripheral neuropathy is caused by off target inhibition of HtrA2/Omi. Further research is needed to understand the side effects of PIs. Disclosures: Senn: Millennium Pharmaceuticals, Inc.: Employment. Csizmadia:Millennium Pharmaceuticals, Inc.: Employment. Hales:Millennium Pharmaceuticals, Inc.: Employment. Dick:Millennium Pharmaceuticals, Inc.: Employment. Kadambi:Millennium Pharmaceuticals, Inc.: Employment.
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Balakrishnan, Meenakshi P., Lucia Cilenti, Zineb Mashak, Paiyal Popat, Emad S. Alnemri, and Antonis S. Zervos. "THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 2 (August 2009): H643—H653. http://dx.doi.org/10.1152/ajpheart.00234.2009.
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Omi/HtrA2 is a mitochondrial serine protease that has a dual function: while confined in the mitochondria, it promotes cell survival, but when released into the cytoplasm, it participates in caspase-dependent as well as caspase-independent cell death. To investigate the mechanism of Omi/HtrA2's function, we set out to isolate and characterize novel substrates for this protease. We have identified Thanatos-associated protein 5 (THAP5) as a specific interactor and substrate of Omi/HtrA2 in cells undergoing apoptosis. This protein is an uncharacterized member of the THAP family of proteins. THAP5 has a unique pattern of expression and is found predominantly in the human heart, although a very low expression is also seen in the human brain and muscle. THAP5 protein is localized in the nucleus and, when ectopically expressed, induces cell cycle arrest. During apoptosis, THAP5 protein is degraded, and this process can be blocked using a specific Omi/HtrA2 inhibitor, leading to reduced cell death. In patients with coronary artery disease, THAP5 protein levels substantially decrease in the myocardial infarction area, suggesting a potential role of this protein in human heart disease. This work identifies human THAP5 as a cardiac-specific nuclear protein that controls cell cycle progression. Furthermore, during apoptosis, THAP5 is cleaved and removed by the proapoptotic Omi/HtrA2 protease. Taken together, we provide evidence to support that THAP5 and its regulation by Omi/HtrA2 provide a new link between cell cycle control and apoptosis in cardiomyocytes.
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Zhang, Yong, Wen-Bin Dong, Li Qing-Ping, Chun-Liang Deng, Tao Xiong, Xiao-Ping Lei, and Lin Guo. "The role of Omi/HtrA2 protease in neonatal postasphyxial serum-induced apoptosis in human kidney proximal tubule cells." Archives of Biological Sciences 64, no. 2 (2012): 435–44. http://dx.doi.org/10.2298/abs1202435z.
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Omi/HtrA2, a proapoptotic mitochondrial serine protease, is involved in both caspase-dependent and caspaseindependent apoptosis. A growing body of evidence indicates that Omi/HtrA2 plays an important role in the pathogenesis of a variety of ischemia-reperfusion (I/R) injuries. However, the role of Omi/HtrA2 in renal injuries that occur in neonates with asphyxia remains unknown. The present study was designed to investigate whether Omi/HtrA2 plays an important role in the types of renal injuries that are induced by neonatal postasphyxial serum. Human renal proximal tubular cell line (HK-2) cells were used as targets. A 20% serum taken from neonates one day after asphyxia was applied to target cells as an attacking factor. We initially included control and postasphyxial serum-attacked groups and later included a ucf-101 group in the study. In the postasphyxial serum-treated group, cytosolic Omi/HtrA2 and caspase-3 expression in HK-2 cells was significantly higher than in the control group. Moreover, the concentration of cytosolic caspase-3 was found to be markedly decreased in HK-2 cells in the ucf-101 group. Our results suggest both that postasphyxial serum has a potent apoptosis-inducing effect on HK-2 cells and that this effect can be partially blocked by ucf-101. Taken together, our results demonstrate for the first time that postasphyxial serum from neonates results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it promotes HK-2 cell apoptosis via a protease activity-dependent, caspase-mediated pathway.
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Zhang, Yong, Wen-Bin Dong, Qing-Ping Li, Chun-Liang Deng, Tao Xiong, Xiao-Ping Lei, and Lin Guo. "The role of Omi/HtrA2 protease in neonatal postasphyxial serum-induced apoptosis in human kidney proximal tubule cells." Archives of Biological Sciences 64, no. 4 (2012): 1505–14. http://dx.doi.org/10.2298/abs1204505z.
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Omi/HtrA2, a proapoptotic mitochondrial serine protease, is involved in both caspase-dependent and caspaseindependent apoptosis. A growing body of evidence indicates that Omi/HtrA2 plays an important role in the pathogenesis of a variety of ischemia/reperfusion (I/R) injuries. However, the role of Omi/HtrA2 in the renal injuries that occur in neonates with asphyxia remains unknown. The present study was designed to investigate whether Omi/HtrA2 plays an important role in the types of renal injuries that are induced by neonatal postasphyxial serum. Human renal proximal tubular cell line (HK-2) cells were used as targets. A 20% serum taken from neonates one day after asphyxia was applied to the target cells as an attacking factor. We initially included control and postasphyxial-serum-attacked groups and later included a ucf-101 group in the study. In the postasphyxial-serum-treated group, cytosolic Omi/HtrA2 and caspase-3 expression in the HK-2 cells was significantly higher than in the control group. Moreover, the concentration of cytosolic caspase-3 was found to be markedly decreased in HK-2 cells in the ucf-101 group. Our results suggest both that postasphyxial serum has a potent apoptosis-inducing effect on HK-2 cells and that this effect can be partially blocked by ucf-101. Taken together, our results demonstrate for the first time that postasphyxial serum from neonates results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it promotes HK-2 cell apoptosis via a protease activity-dependent, caspasemediated pathway.
Dissertations / Theses on the topic "HtrA2/Omi"
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singh, supriya. "NOVEL PROTEIN-PROTEIN INTERACTIONS REGULATE THE PROTEOLYTIC ACTIVITY OF THE PRO- APOPTOTIC SERINE PROTEASE, OMI/HTRA2." Master's thesis, University of Central Florida, 2005. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4091.
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Omi/HtrA2 is a mitochondrial serine protease with high homology to the bacterial HtrA proteins. Omi promotes caspase-dependent apoptosis by binding and degrading IAPs-inhibitor of apoptosis proteins. Omi can also induce caspase-independent apoptosis but the actual mechanism is still unknown. IAP's are not the only substrates cleaved by Omi. There are at least two more known substrates of Omi, the HAX-1 and the ped/pea-15 proteins. HS1-associated protein X-1 (HAX-1) is a mitochondrial protein, degraded by Omi after induction of caspase-dependent apoptosis. Ped/pea-15 is also an anti-apoptotic protein and is cleaved by Omi after induction of caspase-independent apoptosis. The proteolytic activity of Omi is necessary and essential for its pro-apoptotic function. Recent studies suggest the proteolytic activity of Omi is regulated by specific protein-protein interactions. Presenilin was identified to be such a regulator of Omi. It binds to the PDZ domain of Omi via its carboxy-terminus and this interaction significantly increases the proteolytic activity of the enzyme. My project was aimed to investigate the normal function of Omi in cell death and the mechanism of its regulation by isolating and characterizing novel Omi interactors. I screened a human melanocyte cDNA library using the yeast-two-hybrid system and Omi as the "bait" protein. Human Rad21 protein was isolated as a specific novel interactor of Omi. Human Rad21 interacted with the PDZ domain of Omi, the part of the protein known to be involved in protein-protein interactions. Human Rad21 is a nuclear protein that plays a role in DNA double-strand break repair and sister chromatid cohesion during metaphase. Several reports suggest hRad21 has also a role in apoptosis; it is cleaved by caspase-3 and part of the protein becomes cytoplasmic. Human Rad21 was not cleaved by Omi in vitro and therefore it is unlikely to be a substrate. When tested in a proteolytic assay Rad21 was able to increase the proteolytic activity of Omi. My work suggests a new mechanism whereby Omi and hRad21 can co-operate to induce cell death. This mechanism necessitates direct interaction of hRad21 with the PDZ domain of Omi resulting in increased proteolytic activity of the enzyme.M.S.
Department of Molecular Biology and Microbiology
Burnett College of Biomedical Sciences
Molecular Biology and Microbiology
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Ambivero, Camilla. "The Role of Mitochondrial Omi/HtrA2 Protease in Protein Quality Control and Mitophagy." Doctoral diss., University of Central Florida, 2013. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5754.
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Omi/HtrA2 is a nuclear encoded mitochondrial serine protease with dual and opposite functions that depend entirely on its subcellular localization. During apoptosis it is released to the cytoplasm where it participates in cell death. While confined in the mitochondria it has a pro-survival function that may involve the regulation of protein quality control (PQC) and mitochondrial homeostasis. We used the yeast two-hybrid system to dissect Omi/HtrA2's pathway by identifying novel interactors and substrates. Our studies revealed a novel function of Omi/HtrA2 in the regulation of a Lys-63 deubiquitinating (DUB) complex. In addition, we found the mechanism by which Omi/HtrA2 protease participates in mitophagy by directly regulating the protein level of Mulan E3 ubiquitin ligase, especially during mitochondrial stress. Abro1 is a scaffold protein of the DUB complex known as BRISC (BRCC36 isopeptidase complex). In addition, Abro1 is involved in a cytoprotective pathway and is regulated by Omi/HtrA2. Three specific interactors of Abro1 protein were identified, ATF4, ATF5 and JunD, all members of the activating protein 1 (AP-1) family. We focused our studies on ATF4 since, like Abro1, it is ubiquitously expressed and is important in cell cycle regulation and survival. Abro1's interaction with ATF4 was specific and occurred only when cells were stressed. The significance of this interaction was the translocation of Abro1 from the cytoplasm to the cell nucleus. These results establish a new cytoprotective function of cytoplasmic Omi/HtrA2 as a regulator of the BRISC DUB complex. Furthermore, we have recently identified the mitochondrial Mulan E3 ubiquitin ligase as a substrate of Omi/HtrA2 protease. Mulan, along with MARCH5/MITOL and RNF185, are the only three mitochondrial E3 ubiquitin ligases identified thus far. The function of Mulan has been linked to cell growth, cell death, and autophagy/mitophagy. To investigate Mulan's function and its control by Omi/HtrA2, E2 conjugating enzymes that form a complex with Mulan E3 ligase were identified. Four specific interacting E2s were isolated, namely Ube2E2, Ube2E3, Ube2G2, and Ube2L3. To identify substrates for each unique Mulan-E2 complex, fusion baits were used in a modified yeast two-hybrid screen. Our results suggest that Mulan participates in various pathways, depending on the nature of its E2 conjugating enzyme partner. One of the interactors isolated against the Mulan-Ube2E3 bait was the GABARAP (GABAA receptor-associated protein), a member of the Atg8 family. We characterized this interaction both in vitro and in vivo and its potential role in mitophagy. Our studies defined a new pathway by which Mulan participates in mitophagy by recruiting GABARAP to the mitochondria.Ph.D.
Doctorate
Molecular Biology and Microbiology
Medicine
Biomedical Sciences
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Stratico, Valerie Anne. "CHARACTERIZATION OF A NOVEL INTERACTOR/SUBSTRATE FOR THE PRO-APOPTOTIC SERINE PROTEASE OMI/HTRA2." Master's thesis, University of Central Florida, 2004. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4400.
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OmiHtrA2 is a highly conserved mammalian serine protease that belongs to the HtrA family of proteins. Omi shares homology with the bacterially expressed heat shock protease HtrA, which functions as a protease at higher temperatures and a chaperone at lower temperatures. Additionally, Omi shares sequence similarity with the mammalian homologs L56/HtrA1 and PRSP/HtrA3. Omi was first isolated as an interacting protein of Mxi2, an alternatively spliced form of the p38 stress-activated kinase, using a modified yeast two-hybrid system. Omi localizes in the mitochondria and in response to apoptotic stimuli the mature form of this protein translocates to the cytoplasm. In the cytoplasm Omi participates in both the caspase-dependent as well as caspase-independent apoptosis. Additionally, recent studies suggest that Omi may have another unique function, maintaining homeostasis within the mitochondria. In an effort to further elucidate the function of Omi, a yeast two-hybrid screening was performed to isolate novel interacting proteins. This screening identified a novel protein (HOPS), as a specific interactor of Omi. The predicted amino acid sequence of this protein does not provide any information about its potential function in mammalian cells. However, experiments show that HOPS is cleaved in vitro by Omi. Furthermore, in response to apoptotic stimuli, HOPS is also degraded in vivo. This study suggests that HOPS could be a physiological substrate of Omi that is cleaved and removed during apoptosis.M.S.
Department of Molecular Biology and Microbiology
Health and Public Affairs
Molecular Biology and Microbiology
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Ward, Nathan. "Isolation and characterization of a novel substrate for the pro-apoptotic Omi/HtrA2 protease." Honors in the Major Thesis, University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETH/id/635.
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Omi, also known as HtrA2, is a mammalian pro-apoptotic mitochondrial protein and a member of the HtrA (high temperature requirement A) family of serine proteases. Omi promotes the caspase-dependent apoptotic pathway through cleavage of IAPs (inhibitor of apoptosis proteins); this cleavage inactivates IAPs and facilitates caspase activity. Omi's proteolytic activity is necessary and essential for its pro-apoptotic function. This study is aimed to further understand the role of Omi in the cytoplasm by using the yeast two-hybrid system to identify novel Omi interactors/substrates. A HeLa (cervical carcinoma cell line) cDNA library was screened using Omi as a "bait" protein. One of the proteins indentified in this screen as a strong Omi interactor was the S5a protein and was selected for further analysis. S5a is a soluble cytosolic mammalian protein and a component of the proteasome's 19S regulatory subunit. The proteasome is a large cytosolic protein complex responsible for the controlled degradation of damaged or denatured cellular proteins. Further characterization of the interaction through an in vitro proteolytic assay demonstrated that Omi can cleaves recombinant S5a protein. This data suggests that S5a is a bona fide substrate of Omi that is degraded upon induction of apoptosis. It also provides a new mechanism that leads to the inactivation of the proteasome during cell death.B.S.
Bachelors
Burnett School of Biomedical Sciences
Biotechnology
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Klupsch, Kristina. "Regulation and function of the mitochondrial protease HtrA2/Omi in the control of cell death." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1444896/.
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The serine protease HtrA2 is released from mitochondria following apoptotic stimuli. Once in the cytosol, HtrA2 has been implicated in promoting cell death by a caspase-dependent and -independent mechanism. However, mice lacking expression of HtrA2 show no evidence of reduced rates of cell death. On the contrary, loss of HtrA2 causes mitochondrial dysfunction leading to a neurodegenerative disorder with parkinsonian features. This suggests that the protease function of HtrA2 in the mitochondria, and not its pro-apoptotic action in the cytosol, is critical. Mammalian HtrA2 is therefore likely to function in vivo in a manner similar to its bacterial homologues, which are involved in protection against cell stress. The bacterial DegS homologue senses unfolded proteins, activating a proteolytic cascade leading to induction of stress response genes. Transcriptional profiling of wild type and HtrA2 knockout (KO) cells identified the stress-inducible transcription factor CHOP being differentially regulated when mitochondrial stress was triggered. CHOP up-regulation was found in HtrA2 KO mouse brains but not in other tissues. Transcriptional profiling of brain tissue revealed a number of putative ATF4 target genes being up-regulated in HtrA2 KO, among these CHOP. Promoter analysis identified a C/EBP-ATF composite site in the majority of the genes within this signature. Therefore, loss of HtrA2 might impact on nuclear gene expression specifically in brain, subverting normal cellular homeostasis leading to disease. In humans, point mutations in HtrA2 are a susceptibility factor for Parkinson's disease (PD) resulting in partial loss of proteolytic activity. Affinity purification shows that the mitochondrial kinase PINK1 interacts with HtrA2. PINK1 mutations are associated with the PARK6 PD susceptibility locus. HtrA2 is phosphorylated in a PINK1-dependent manner at residues adjacent to positions found mutated in PD patients. Phosphorylation of HtrA2 and thereby modulation of its proteolytic activity seems necessary for the function of HtrA2 in the mitochondria contributing to increased resistance of cells to mitochondrial stress.
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Maus, Frank [Verfasser]. "Die Interaktion zwischen OMI/HtrA2 und NG2 in oligodendroglialen Vorläuferzellen : NG2 und Homöostase? / Frank Maus." Mainz : Universitätsbibliothek Mainz, 2018. http://d-nb.info/1155509331/34.
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Balakrishnan, Meenakshi Puthucode. "Studies on a novel human cardiospecific transcription factor and its involvement in Omi/HtrA2 mediated cell death." Doctoral diss., University of Central Florida, 2010. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4649.
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Omi/HtrA2 is a mitochondrial serine protease that is known to translocate to the cytoplasm upon induction of apoptosis and to activate caspase-dependent and caspase-independent cell death. The molecular mechanism of Omi/HtrA2's function is not clear but involves degradation of specific substrates. These substrates include cytoplasmic, mitochondrial, as well as nuclear proteins. We have pubmedisolated a new Omi/HtrA2 interactor, the THAP5 protein. THAP5 is a fifth member of a large family of transcription factors that are involved in cell proliferation, apoptosis, cell cycle control, chromosome segregation, chromatin modification and transcriptional regulation. THAP5 is an approximately 50kDa nuclear protein, with a restricted pattern of expression. Furthermore, there is no mouse or rat homolog for this protein. THAP5 mRNA is highly expressed in the human heart but some expression is also seen in the brain and skeletal muscle. The normal function of THAP5 in the heart or heart disease is unknown. THAP5 protein level is significantly reduced in the myocardial infarction (MI) area in the heart of patients with coronary artery disease (CAD). This part of the heart sustains most of the cellular damage and apoptosis. Our data clearly show that THAP5 is a specific substrate of the proapoptotic Omi/HtrA2 protease and is cleaved and removed during cell death. The molecular mechanism of THAP5's function is unclear. THAP5 can bind to a specific DNA sequence and repress transcription of a reporter gene. Our work suggests that THAP5 is a tissue specific transcriptional repressor that plays an important role in the normal function of the human heart as well as in the development of heart disease.ID: 029050522; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Thesis (Ph.D.)--University of Central Florida, 2010.; Includes bibliographical references (p. 68-79).
Ph.D.
Doctorate
Burnett School of Biomedical Sciences
Medicine
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Kadner, Karen [Verfasser]. "Expressionsprofil und prognostische Bedeutung der mitochondrialen IAP Antagonisten Smac/DIABLO und Omi/HtrA2 im klarzelligen Nierenzellkarzinom / Karen Kadner." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2010. http://d-nb.info/1024005569/34.
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CICERI, DALILA. "Cell-based analysis of dynamic aspects of molecular mechanism involved in the pathogenesis of Parkinson's disease." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2010. http://hdl.handle.net/10281/10302.
Full textAbstract:
Intracytoplasmic protein aggregates called Lewy Bodies (LB) characterize the neurodegeneration in Parkinson’s Disease (PD). However, whether aggregates are linked to cell death or they represent a protective mechanism is debated. Recent studies suggest that autophagy participates in the degradation of cytoplasmic protein inclusions. Moreover, growing evidence shows that mitochondrial impairments and altered mitochondrial fission and fusion play a role in the pathogenesis of PD.
Synphilin-1 is a protein that is present in LB and that interacts with key elements of PD pathogenesis, such as α-synuclein. Overexpression of synphilin-1 in various cellular models leads to cytoplasmatic inclusions that fulfil the criteria of aggresomes, dynamic structures formed under proteolytic stress. HtrA2/Omi is a mitochondrial protease that is thought to be involved in protection of mitochondria against stress in physiological conditions, besides its pro-apoptotic function under apoptosis induction. Loss of HtrA2/Omi function leads to neurodegeneration in mouse models. Mutations in both synphilin-1 and HtrA2/Omi have been found in PD patients.
We used HEK293 cells overexpressing wild type (WT) or R621C mutant synphilin-1 to evaluate if autophagy activation may influence cell viability by modulating synphilin-1 inclusions. Moreover, we studied also the effects synphilin-1-overexpression and aggregation on mitochondria. In addition, we evaluated the consequences of loss of HtrA2/Omi on mitochondrial function and morphology in fibroblasts from knockout mice, as well as in HeLa cells and in Drosophila melanogaster S2R+ cells.
We observed co-localization of synphilin-1 inclusions with autophagic structures and the pharmacological activation of autophagy was effective in reducing the percentage of cells bearing synphilin-1 inclusions. However, this treatment couldn’t protect the cells from apoptosis induced by proteasome inhibition. Synphilin-1-overexpressing cells revealed higher levels of mitochondrial reactive oxygen species (ROS) and reduced mitochondrial membrane potential (MMP) compared to empty vector controls.
HtrA2/Omi deficiency caused accumulation of ROS within mitochondria and reduced MMP as well, together with morphological alterations of the mitochondria. Interestingly, we observed a selective up-regulation of the fusion factor OPA1 in cells lacking HtrA2/Omi and co-immunoprecipitation experiments showed that these two proteins can physically interact.
To conclude, our findings support the view that aggresomes are actively built to remove excesses of noxious proteins; however, the enhancement of their clearance via autophagy is not sufficient to protect against proteasome inhibition and mitochondrial impairments in the presence of high levels of aggregate-prone proteins.
Concerning HtrA2/Omi, we confirmed previous reports showing an involvement of this protease in maintaining mitochondrial homeostasis and we reported for the first time a direct effect of loss of HtrA2/Omi on mitochondrial morphology. Finally, we showed a novel role of HtrA2/Omi in the modulation of OPA1.
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Chen, Jing [Verfasser], Katrin [Akademischer Betreuer] Marcus, and Dirk [Akademischer Betreuer] Wolters. "Molecularly imprinted polymers for the analysis of protein phosphorylation and the role of HtrA2/Omi protein in Parkinson's disease / Jing Chen. Gutachter: Katrin Marcus ; Dirk Wolters." Bochum : Ruhr-Universität Bochum, 2016. http://d-nb.info/1089006411/34.
Full textConference papers on the topic "HtrA2/Omi"
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Ghavami, S., MM Mutawe, KD McNeill, D. Schaafsma, H. Unruh, and AJ Halayko. "Simvastatin Induces Apoptosis of Airway Mesenchymal Cells Via a Novel p53-Dependent Pathway That Includes Selective Release of Smac/Diablo and Omi/HtrA2 from Mitochondria." In American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California. American Thoracic Society, 2009. http://dx.doi.org/10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a2070.
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