Artículos de revistas: "Gbp2"

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Clough, Barbara, Ryan Finethy, Rabia T. Khan, Daniel Fisch, Sarah Jordan, Harshil Patel, Jörn Coers y Eva-Maria Frickel. "C57BL/6 and 129 inbred mouse strains differ in Gbp2 and Gbp2b expression in response to inflammatory stimuli in vivo". Wellcome Open Research 4 (20 de agosto de 2019): 124. http://dx.doi.org/10.12688/wellcomeopenres.15329.1.

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Background: Infections cause the production of inflammatory cytokines such as Interferon gamma (IFNγ). IFNγ in turn prompts the upregulation of a range of host defence proteins including members of the family of guanylate binding proteins (Gbps). In humans and mice alike, GBPs restrict the intracellular replication of invasive microbes and promote inflammation. To study the physiological functions of Gbp family members, the most commonly chosen in vivo models are mice harbouring loss-of-function mutations in either individual Gbp genes or the entire Gbp gene cluster on mouse chromosome 3. Individual Gbp deletion strains differ in their design, as some strains exist on a pure C57BL/6 genetic background, while other strains contain a 129-derived genetic interval encompassing the Gbp gene cluster on an otherwise C57BL/6 genetic background. Methods: To determine whether the presence of 129 alleles of paralogous Gbps could influence the phenotypes of 129-congenic Gbp-deficient strains, we studied the expression of Gbps in both C57BL/6J and 129/Sv mice following in vivo stimulation with adjuvants and after infection with either Toxoplasma gondii or Shigella flexneri. Results: We show that C57BL/6J relative to 129/Sv mice display moderately elevated expression of Gbp2, but more prominently, are also defective for Gbp2b (formerly Gbp1) mRNA induction upon immune priming. Notably, Toxoplasma infections induce robust Gbp2b protein expression in both strains of mice, suggestive of a Toxoplasma-activated mechanism driving Gbp2b protein translation. We further find that the higher expression of Gbp2b mRNA in 129/Sv mice correlates with a gene duplication event at the Gbp2b locus resulting in two copies of the Gbp2b gene on the haploid genome of the 129/Sv strain. Conclusions: Our findings demonstrate functional differences between 129 and C57BL/6 Gbp alleles which need to be considered in the design and interpretation of studies utilizing mouse models, particularly for phenotypes influenced by Gbp2 or Gbp2b expression.

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Feeley, Eric M., Danielle M. Pilla-Moffett, Erin E. Zwack, Anthony S. Piro, Ryan Finethy, Joseph P. Kolb, Jennifer Martinez, Igor E. Brodsky y Jörn Coers. "Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems". Proceedings of the National Academy of Sciences 114, n.º 9 (13 de febrero de 2017): E1698—E1706. http://dx.doi.org/10.1073/pnas.1615771114.

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Many invasive bacteria establish pathogen-containing vacuoles (PVs) as intracellular niches for microbial growth. Immunity to these infections is dependent on the ability of host cells to recognize PVs as targets for host defense. The delivery of several host defense proteins to PVs is controlled by IFN-inducible guanylate binding proteins (GBPs), which themselves dock to PVs through poorly characterized mechanisms. Here, we demonstrate that GBPs detect the presence of bacterial protein secretion systems as “patterns of pathogenesis” associated with PVs. We report that the delivery of GBP2 to Legionella-containing vacuoles is dependent on the bacterial Dot/Icm secretion system, whereas the delivery of GBP2 to Yersinia-containing vacuoles (YCVs) requires hypersecretion of Yersinia translocon proteins. We show that the presence of bacterial secretion systems directs cytosolic carbohydrate-binding protein Galectin-3 to PVs and that the delivery of GBP1 and GBP2 to Legionella-containing vacuoles or YCVs is substantially diminished in Galectin-3–deficient cells. Our results illustrate that insertion of bacterial secretion systems into PV membranes stimulates Galectin-3–dependent recruitment of antimicrobial GBPs to PVs as part of a coordinated host defense program.

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Legewie, Larissa, Jennifer Loschwitz, Nora Steffens, Martin Prescher, Xue Wang, Sander H. J. Smits, Lutz Schmitt, Birgit Strodel, Daniel Degrandi y Klaus Pfeffer. "Biochemical and structural characterization of murine GBP7, a guanylate binding protein with an elongated C-terminal tail". Biochemical Journal 476, n.º 21 (5 de noviembre de 2019): 3161–82. http://dx.doi.org/10.1042/bcj20190364.

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Abstract Guanylate-binding proteins (GBPs) constitute a family of interferon-inducible guanosine triphosphatases (GTPases) that are key players in host defense against intracellular pathogens ranging from protozoa to bacteria and viruses. So far, human GBP1 and GBP5 as well as murine GBP2 (mGBP2) have been biochemically characterized in detail. Here, with murine GBP7 (mGBP7), a GBP family member with an unconventional and elongated C-terminus is analyzed. The present study demonstrates that mGBP7 exhibits a concentration-dependent GTPase activity and an apparent GTP turnover number of 20 min−1. In addition, fluorescence spectroscopy analyses reveal that mGBP7 binds GTP with high affinity (KD = 0.22 µM) and GTPase activity assays indicate that mGBP7 hydrolyzes GTP to GDP and GMP. The mGBP7 GTPase activity is inhibited by incubation with γ-phosphate analogs and a K51A mutation interfering with GTP binding. SEC-MALS analyses give evidence that mGBP7 forms transient dimers and that this oligomerization pattern is not influenced by the presence of nucleotides. Moreover, a structural model for mGBP7 is provided by homology modeling, which shows that the GTPase possesses an elongated C-terminal (CT) tail compared with the CaaX motif-containing mGBP2 and human GBP1. Molecular dynamics simulations indicate that this tail has transmembrane characteristics and, interestingly, confocal microscopy analyses reveal that the CT tail is required for recruitment of mGBP7 to the parasitophorous vacuole of Toxoplasma gondii.

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Srinivasachar Badarinarayan, Smitha, Irina Shcherbakova, Simon Langer, Lennart Koepke, Andrea Preising, Dominik Hotter, Frank Kirchhoff, Konstantin M. J. Sparrer, Gunnar Schotta y Daniel Sauter. "HIV-1 infection activates endogenous retroviral promoters regulating antiviral gene expression". Nucleic Acids Research 48, n.º 19 (6 de octubre de 2020): 10890–908. http://dx.doi.org/10.1093/nar/gkaa832.

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Abstract Although endogenous retroviruses (ERVs) are known to harbor cis-regulatory elements, their role in modulating cellular immune responses remains poorly understood. Using an RNA-seq approach, we show that several members of the ERV9 lineage, particularly LTR12C elements, are activated upon HIV-1 infection of primary CD4+ T cells. Intriguingly, HIV-1-induced ERVs harboring transcription start sites are primarily found in the vicinity of immunity genes. For example, HIV-1 infection activates LTR12C elements upstream of the interferon-inducible genes GBP2 and GBP5 that encode for broad-spectrum antiviral factors. Reporter assays demonstrated that these LTR12C elements drive gene expression in primary CD4+ T cells. In line with this, HIV-1 infection triggered the expression of a unique GBP2 transcript variant by activating a cryptic transcription start site within LTR12C. Furthermore, stimulation with HIV-1-induced cytokines increased GBP2 and GBP5 expression in human cells, but not in macaque cells that naturally lack the GBP5 gene and the LTR12C element upstream of GBP2. Finally, our findings suggest that GBP2 and GBP5 have already been active against ancient viral pathogens as they suppress the maturation of the extinct retrovirus HERV-K (HML-2). In summary, our findings uncover how human cells can exploit remnants of once-infectious retroviruses to regulate antiviral gene expression.

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Yu, Peifa, Yang Li, Yunlong Li, Zhijiang Miao, Maikel P. Peppelenbosch y Qiuwei Pan. "Guanylate-binding protein 2 orchestrates innate immune responses against murine norovirus and is antagonized by the viral protein NS7". Journal of Biological Chemistry 295, n.º 23 (30 de abril de 2020): 8036–47. http://dx.doi.org/10.1074/jbc.ra120.013544.

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Noroviruses are the main causative agents of acute viral gastroenteritis, but the host factors that restrict their replication remain poorly identified. Guanylate-binding proteins (GBPs) are interferon (IFN)-inducible GTPases that exert broad antiviral activity and are important mediators of host defenses against viral infections. Here, we show that both IFN-γ stimulation and murine norovirus (MNV) infection induce GBP2 expression in murine macrophages. Results from loss- and gain-of-function assays indicated that GBP2 is important for IFN-γ–dependent anti-MNV activity in murine macrophages. Ectopic expression of MNV receptor (CD300lf) in human HEK293T epithelial cells conferred susceptibility to MNV infection. Importantly, GBP2 potently inhibited MNV in these human epithelial cells. Results from mechanistic dissection experiments revealed that the N-terminal G domain of GBP2 mediates these anti-MNV effects. R48A and K51A substitutions in GBP2, associated with loss of GBP2 GTPase activity, attenuated the anti-MNV effects of GBP2. Finally, we found that nonstructural protein 7 (NS7) of MNV co-localizes with GBP2 and antagonizes the anti-MNV activity of GBP2. These findings reveal that GBP2 is an important mediator of host defenses against murine norovirus.

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Liu, Bo, Rongfei Huang, Tingting Fu, Ping He, Chengyou Du, Wei Zhou, Ke Xu y Tao Ren. "GBP2 as a potential prognostic biomarker in pancreatic adenocarcinoma". PeerJ 9 (11 de mayo de 2021): e11423. http://dx.doi.org/10.7717/peerj.11423.

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Background Pancreatic adenocarcinoma (PAAD) is a disease with atypical symptoms, an unfavorable response to therapy, and a poor outcome. Abnormal guanylate-binding proteins (GBPs) play an important role in the host’s defense against viral infection and may be related to carcinogenesis. In this study, we sought to determine the relationship between GBP2 expression and phenotype in patients with PAAD and explored the possible underlying biological mechanism. Method We analyzed the expression of GBP2 in PAAD tissues using a multiple gene expression database and a cohort of 42 PAAD patients. We evaluated GBP2’s prognostic value using Kaplan–Meier analysis and the Cox regression model. GO and KEGG enrichment analysis, co-expression analysis, and GSEA were performed to illustrate the possible underlying biological mechanism. CIBERSORT and the relative expression of immune checkpoints were used to estimate the relationship between GBP2 expression and tumor immunology. Result GBP2 was remarkably overexpressed in PAAD tissue. The overexpression of GBP2 was correlated with an advanced T stage and poor overall survival (OS) and GBP2 expression was an independent risk factor for OS in PAAD patients. Functional analysis demonstrated that positively co-expressed genes of GBP2 were closely associated with pathways in cancer and the NOD-like receptor signaling pathway. Most of the characteristic immune checkpoints, including PDCD1, PDCDL1, CTLA4, CD80, TIGIT, LAG3, IDO2, and VISTA, were significantly expressed in the high-GBP2 expression group compared with the low-GBP2 expression group. Conclusion GBP2 acted as a potential prognostic biomarker and was associated with immune infiltration and the expression of immune checkpoints in PAAD.

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Ohshima, Jun, Miwa Sasai, Jianfa Liu, Kazuo Yamashita, Ji Su Ma, Youngae Lee, Hironori Bando et al. "RabGDIα is a negative regulator of interferon-γ–inducible GTPase-dependent cell-autonomous immunity to Toxoplasma gondii". Proceedings of the National Academy of Sciences 112, n.º 33 (3 de agosto de 2015): E4581—E4590. http://dx.doi.org/10.1073/pnas.1510031112.

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IFN-γ orchestrates cell-autonomous host defense against various intracellular vacuolar pathogens. IFN-γ–inducible GTPases, such as p47 immunity-related GTPases (IRGs) and p65 guanylate-binding proteins (GBPs), are recruited to pathogen-containing vacuoles, which is important for disruption of the vacuoles, culminating in the cell-autonomous clearance. Although the positive regulation for the proper recruitment of IRGs and GBPs to the vacuoles has been elucidated, the suppressive mechanism is unclear. Here, we show that Rab GDP dissociation inhibitor α (RabGDIα), originally identified as a Rab small GTPase inhibitor, is a negative regulator of IFN-γ–inducible GTPases in cell-autonomous immunity to the intracellular pathogen Toxoplasma gondii. Overexpression of RabGDIα, but not of RabGDIβ, impaired IFN-γ–dependent reduction of T. gondii numbers. Conversely, RabGDIα deletion in macrophages and fibroblasts enhanced the IFN-γ–induced clearance of T. gondii. Furthermore, upon a high dose of infection by T. gondii, RabGDIα-deficient mice exhibited a decreased parasite burden in the brain and increased resistance in the chronic phase than did control mice. Among members of IRGs and GBPs important for the parasite clearance, Irga6 and Gbp2 alone were more frequently recruited to T. gondii-forming parasitophorous vacuoles in RabGDIα-deficient cells. Notably, Gbp2 positively controlled Irga6 recruitment that was inhibited by direct and specific interactions of RabGDIα with Gbp2 through the lipid-binding pocket. Taken together, our results suggest that RabGDIα inhibits host defense against T. gondii by negatively regulating the Gbp2–Irga6 axis of IFN-γ–dependent cell-autonomous immunity.

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Zhang, Juan, Yu Zhang, Wenshuang Wu, Fang Wang, Xinyu Liu, Guanghou Shui y Chunlai Nie. "Guanylate-binding protein 2 regulates Drp1-mediated mitochondrial fission to suppress breast cancer cell invasion". Cell Death & Disease 8, n.º 10 (octubre de 2017): e3151-e3151. http://dx.doi.org/10.1038/cddis.2017.559.

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Abstract Guanylate-binding protein 2 (GBP2) is a member of the large GTPase superfamily that is strongly induced by interferon-γ (IFN-γ). Although the biochemical characteristics of GBP2 have been reported in detail, its biological function has not been thoroughly elucidated to date. To the best of our knowledge, this study presents the first demonstration that GBP2 inhibits mitochondrial fission and cell metastasis in breast cancer cells both in vitro and in vivo. Our previous work demonstrated that dynamin-related protein 1 (Drp1)-dependent mitochondrial fission has a key role in breast cancer cell invasion. In this study, we demonstrate that GBP2 binds directly to Drp1. Elimination of Drp1 by shRNA or Mdivi-1 (a Drp1-specific inhibitor) suppressed GBP2’s regulatory function. Furthermore, GBP2 blocks Drp1 translocation from the cytosol to mitochondria, thereby attenuating Drp1-dependent mitochondrial fission and breast cancer cell invasion. In summary, our data provide new insights into the function and molecular mechanisms underlying GBP2’s regulation of breast cancer cell invasion.

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Ma, Guojian, Jing Huang, Nunu Sun, Xiangdong Liu, Mengjin Zhu, Zhenfang Wu y Shuhong Zhao. "Molecular characterization of the porcine GBP1 and GBP2 genes". Molecular Immunology 45, n.º 10 (mayo de 2008): 2797–807. http://dx.doi.org/10.1016/j.molimm.2008.02.007.

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Wang, Haizhou, Yabo Zhou, Yangyang Zhang, Shilin Fang, Meng Zhang, Haiou Li, Fei Xu et al. "Subtyping of microsatellite stability colorectal cancer reveals guanylate binding protein 2 (GBP2) as a potential immunotherapeutic target". Journal for ImmunoTherapy of Cancer 10, n.º 4 (abril de 2022): e004302. http://dx.doi.org/10.1136/jitc-2021-004302.

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BackgroundsProficient-mismatch-repair or microsatellite stability (pMMR/MSS) colorectal cancer (CRC) has limited efficacy for immune checkpoint blockade (ICB) therapy and its underlying mechanism remains unclear. Guanylate binding protein 2 (GBP2) is a member of the GTPase family and is crucial to host immunity against pathogens. However, the correlations between GBP2 and immunosurveillance and immunotherapy for pMMR/MSS CRC have not been reported.MethodsUnsupervised clustering was employed to classify immune class and non-immune class in 1424 pMMR/MSS patients from six independent public datasets. This binary classification was validated using immune cells or response related signatures. The correlation between GBP2 and immune microenvironment was explored using well-established biological algorithms, multiplex immunohistochemistry (mIHC), in vitro and in vivo experiments.ResultsWe classified 1424 pMMR/MSS CRC patients into two classes, ‘immune’ and ‘non-immune’, and GBP2 was identified as a gene of interest. We found that lower GBP2 expression was correlated with poor prognosis and metastasis. GBP2 expression was also upregulated in the immune class and highly associated with interferon-γ (IFN-γ) signaling pathway and CD8 +T cell infiltration using gene set enrichment analysis, gene ontology analysis, single-cell sequencing and mIHC. Moreover, reduced GBP2 expression inhibited the antigen processing and presentation machinery and CXCL10/11 expression in MSS CRC cells on IFN-γ stimulation. A Transwell assay revealed that deletion of GBP2 in murine MSS CRC cells reduced CD8 +T cell migration. Mechanistically, GBP2 promoted signal transducer and transcription activator 1 (STAT1) phosphorylation by competing with SHP1 for binding to STAT1 in MSS CRC cells. Finally, an unsupervised subclass mapping (SubMap) algorithm showed that pMMR/MSS patients with high GBP2 expression may correlate with a favorable response to anti-PD-1 therapy. We further confirmed that GBP2 knockout reduced CD8 +T cell infiltration and blunted the efficacy of PD-1 blockade in tumor-bearing mice.ConclusionsOur study reveals that pMMR/MSS CRC is immunogenically heterogeneous and that GBP2 is a promising target for combinatorial therapy with ICB.

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Cui, Wen, Elisabeth Braun, Wei Wang, Jinhong Tang, Yanyan Zheng, Benjamin Slater, Na Li et al. "Structural basis for GTP-induced dimerization and antiviral function of guanylate-binding proteins". Proceedings of the National Academy of Sciences 118, n.º 15 (5 de abril de 2021): e2022269118. http://dx.doi.org/10.1073/pnas.2022269118.

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Guanylate-binding proteins (GBPs) form a family of dynamin-related large GTPases which mediate important innate immune functions. They were proposed to form oligomers upon GTP binding/hydrolysis, but the molecular mechanisms remain elusive. Here, we present crystal structures of C-terminally truncated human GBP5 (hGBP51–486), comprising the large GTPase (LG) and middle (MD) domains, in both its nucleotide-free monomeric and nucleotide-bound dimeric states, together with nucleotide-free full-length human GBP2. Upon GTP-loading, hGBP51–486 forms a closed face-to-face dimer. The MD of hGBP5 undergoes a drastic movement relative to its LG domain and forms extensive interactions with the LG domain and MD of the pairing molecule. Disrupting the MD interface (for hGBP5) or mutating the hinge region (for hGBP2/5) impairs their ability to inhibit HIV-1. Our results point to a GTP-induced dimerization mode that is likely conserved among all GBP members and provide insights into the molecular determinants of their antiviral function.

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Liang, Hai Po H., Edward J. Kerschen, Irene Hernandez, Sreemanti Basu, Mark Zogg, Fady Botros, Shuang Jia et al. "EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice". Blood 125, n.º 18 (30 de abril de 2015): 2845–54. http://dx.doi.org/10.1182/blood-2014-11-610717.

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Abstract Infection and inflammation are invariably associated with activation of the blood coagulation mechanism, secondary to the inflammation-induced expression of the coagulation initiator tissue factor (TF) on innate immune cells. By investigating the role of cell-surface receptors for coagulation factors in mouse endotoxemia, we found that the protein C receptor (ProcR; EPCR) was required for the normal in vivo and in vitro induction of lipopolysaccharide (LPS)-regulated gene expression. In cultured bone marrow–derived myeloid cells and in monocytic RAW264.7 cells, the LPS-induced expression of functionally active TF, assembly of the ternary TF-VIIa-Xa initiation complex of blood coagulation, and the EPCR-dependent activation of protease-activated receptor 2 (PAR2) by the ternary TF-VIIa-Xa complex were required for the normal LPS induction of messenger RNAs encoding the TLR3/4 signaling adaptor protein Pellino-1 and the transcription factor interferon regulatory factor 8. In response to in vivo challenge with LPS, mice lacking EPCR or PAR2 failed to fully initiate an interferon-regulated gene expression program that included the Irf8 target genes Lif, Iigp1, Gbp2, Gbp3, and Gbp6. The inflammation-induced expression of TF and crosstalk with EPCR, PAR2, and TLR4 therefore appear necessary for the normal evolution of interferon-regulated host responses.

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Yu, Shuye, Xiaoting Yu, Lili Sun, Yanwen Zheng, Lili Chen, Hui Xu, Jing Jin, Qing Lan, Clark C. Chen y Ming Li. "GBP2 enhances glioblastoma invasion through Stat3/fibronectin pathway". Oncogene 39, n.º 27 (9 de junio de 2020): 5042–55. http://dx.doi.org/10.1038/s41388-020-1348-7.

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Niedelman, Wendy, Joris K. Sprokholt, Barbara Clough, Eva-Maria Frickel y Jeroen P. J. Saeij. "Cell Death of Gamma Interferon-Stimulated Human Fibroblasts upon Toxoplasma gondii Infection Induces Early Parasite Egress and Limits Parasite Replication". Infection and Immunity 81, n.º 12 (16 de septiembre de 2013): 4341–49. http://dx.doi.org/10.1128/iai.00416-13.

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ABSTRACTThe intracellular protozoan parasiteToxoplasma gondiiis a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance toToxoplasmais dependent on gamma interferon (IFN-γ) activation of both hematopoietic and nonhematopoietic cells. Although IFN-γ-induced innate immunity in nonhematopoietic cells has been extensively studied in mice, it remains unclear what resistance mechanisms are relied on in nonhematopoietic human cells. Here, we report an IFN-γ-induced mechanism of resistance toToxoplasmain primary human foreskin fibroblasts (HFFs) that does not depend on the deprivation of tryptophan or iron. In addition, infection is still controlled in HFFs deficient in the p65 guanylate binding proteins GBP1 or GBP2 and the autophagic protein ATG5. Resistance is coincident with host cell death that is not dependent on the necroptosis mediator RIPK3 or caspases and is correlated with early egress of the parasite before replication. This IFN-γ-induced cell death and early egress limits replication in HFFs and could promote clearance of the parasite by immune cells.

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Yu, Shuye y Ming Li. "CSIG-20. GBP2 ENHANCES GLIOBLASTOMA INVASION THROUGH STAT3/FIBRONECTION PATHWAY". Neuro-Oncology 20, suppl_6 (noviembre de 2018): vi47. http://dx.doi.org/10.1093/neuonc/noy148.186.

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Lu, Yen-Yun y Heike Krebber. "Nuclear mRNA Quality Control and Cytoplasmic NMD Are Linked by the Guard Proteins Gbp2 and Hrb1". International Journal of Molecular Sciences 22, n.º 20 (19 de octubre de 2021): 11275. http://dx.doi.org/10.3390/ijms222011275.

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Pre-mRNA splicing is critical for cells, as defects in this process can lead to altered open reading frames and defective proteins, potentially causing neurodegenerative diseases and cancer. Introns are removed in the nucleus and splicing is documented by the addition of exon-junction-complexes (EJCs) at exon-exon boundaries. This “memory” of splicing events is important for the ribosome, which translates the RNAs in the cytoplasm. In case a stop codon was detected before an EJC, translation is blocked and the RNA is eliminated by the nonsense-mediated decay (NMD). In the model organism Saccharomyces cerevisiae, two guard proteins, Gbp2 and Hrb1, have been identified as nuclear quality control factors for splicing. In their absence, intron-containing mRNAs leak into the cytoplasm. Their presence retains transcripts until the process is completed and they release the mRNAs by recruitment of the export factor Mex67. On transcripts that experience splicing problems, these guard proteins recruit the nuclear RNA degradation machinery. Interestingly, they continue their quality control function on exported transcripts. They support NMD by inhibiting translation and recruiting the cytoplasmic degradation factors. In this way, they link the nuclear and cytoplasmic quality control systems. These discoveries are also intriguing for humans, as homologues of these guard proteins are present also in multicellular organisms. Here, we provide an overview of the quality control mechanisms of pre-mRNA splicing, and present Gbp2 and Hrb1, as well as their human counterparts, as important players in these pathways.

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Kotov, Dmitri I., Jason S. Mitchell, Thomas Pengo, Christiane Ruedl, Sing Sing Way, Ryan A. Langlois, Brian T. Fife y Marc K. Jenkins. "TCR Affinity Biases Th Cell Differentiation by Regulating CD25, Eef1e1, and Gbp2". Journal of Immunology 202, n.º 9 (11 de marzo de 2019): 2535–45. http://dx.doi.org/10.4049/jimmunol.1801609.

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Martínez-Lumbreras, Santiago, Valerio Taverniti, Silvia Zorrilla, Bertrand Séraphin y José Manuel Pérez-Cañadillas. "Gbp2 interacts with THO/TREX through a novel type of RRM domain". Nucleic Acids Research 44, n.º 1 (23 de noviembre de 2015): 437–48. http://dx.doi.org/10.1093/nar/gkv1303.

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Niu, Pengxia, Sang-Wook Kim, Won-Il Kim y Kwan-Suk Kim. "Association analyses of DNA polymorphisms in immune-related candidate genes GBP1, GBP2, CD163, and CD169 with porcine growth and meat quality traits". Journal of Biomedical Research 16, n.º 2 (junio de 2015): 40–46. http://dx.doi.org/10.12729/jbr.2015.16.2.040.

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Qin, Aiping, De-Hua Lai, Weijun Huang, Mingshui Wu, Xiaoyong Chen, Peng Xiang y Qifa Liu. "Bone Marrow-Derived MSCs Stimulated by IFN-γ Inhibited the Growth of ToxoplasmaGondii Via up-Regulation of GBP1". Blood 124, n.º 21 (6 de diciembre de 2014): 5143. http://dx.doi.org/10.1182/blood.v124.21.5143.5143.

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Abstract Background Mesenchymal stromal cells (MSCs) are a heterogeneous cell population endowed with multi-lineage differentiation potential and extensive immunomodulatory properties. MSCs have been successfully used for prevention and treatment of immune disorders such as graft-versus-host disease. Emerging preclinical studies suggest that MSCs might also protect against infectious challenge. Aims This study aimed to rule out the potential mechanism of human MSCs against Toxoplasma gondii (T. gondii). Methods Human bone marrow-derived MSCs (hMSCs) were pretreated for 24h with a series of concentrations of IFN-γ and then infected with T. gondii strains of variant virulences (virulent RH and avirulent ME49). RNA-seq and westernblots were used to analyze gene and protein expression patterns of hMSCs in IFN-γ-stimulated and unstimulated conditions. The intracellular parasites (with fluorescence labeled) were counted microscopically at multiple time points postinfection. The short hairpin RNA (shRNA) expression was used to generate RNAi of GBP-1, GBP-2 and GBP-5. Results Human MSCs stimulated with IFN-γ were capable to inhibit the growth of T. gondii (eg: at IFN-γ 10ng/ml, the inhibition rates are 26.5% (RH) and 37.5% (ME49) 12hr postinfection) in a dose-dependent manner. Compared with the unstimulated MSCs (controls), IFN-γ treatment at 5, 10, 20ng/ml inhibited T. gondii (ME49) growth by percent of 27.1±7.9, 37.5±6.2, 47.0±7.6 (mean±SD, n=4) 12 hr postinfection and the inhibition rates are 54.5±2.1%, 62.5±4.9% and 78.5±2.1 at 24 hr postinfection, respectively. After 48 hr postinfection, the ratio between parasites per parasitophorous vacuole (PV) containing rosettes and single paraites in IFN-γ-stimulated MSCs was significantly reduced compared with that in the unstimulated MSCs (p<0.01, p<0.01, p<0.001 for ME49 at IFN-γ 5, 10, 20ng/ml, respectively). Furthermore, There was no significant effect of conditioned medium (CM) from IFN-γ-stimulated MSCs on T. gondii growth in comparison with CM from unstimulated MSCs (p=0.74 for RH and p=0.69 for ME49). We observed that the resistance in hMSCs does not depend on IDO (p=0.85 for RH and p=0.79 for ME49). RNA-seq data showed that IFN-γ-inducible p65 guanylate-binding proteins (GBPs) might play pivotal roles in the inhibition of T. gondii growth. Reads per kilobase-pairs per million (RPKM) mean values of GBP1, 2, 5 in IFN-γ-stimulated MSCs are 1093.3, 443.3, 348.2, respectively. By RNAi knockdown, the results showed that silencing of GBP1 (but not GBP2, GBP5) in hMSCs resulted in recovery of T. gondii growth inhibition at 12 hr and 24 hr postinfection (p<0.05 and p<0.001 for ME49). Conclusion: Human MSCs pre-stimulated with IFN-γ inhibited the growth of T. gondii in a dose-dependent manner via up-regulation of GBP-1 expression. Disclosures Liu: the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027): Research Funding; the Technology Plan of Guangdong Province of China (2012B031800403): Research Funding; the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1): Research Funding; Natural Science Foundation of Guangdong Province (S2012010009299): Research Funding; National Public Health Grand Research Foundation (201202017): Research Funding; National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding; National Natural Science Foundation of China (81270647, 81300445, 81200388): Research Funding.

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Zhao, Xiaoyu, Bocheng Yin y Sarah E. Ewald. "Cell death effectors are recruited to Toxoplasma gondii parasite vacuoles targeted by interferon-inducible GTPases in infected dendritic cells". Journal of Immunology 206, n.º 1_Supplement (1 de mayo de 2021): 110.04. http://dx.doi.org/10.4049/jimmunol.206.supp.110.04.

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Abstract Toxoplasma gondii is an obligate intracellular pathogen whose ability to grow and evade cell autonomous immunity depends on the parasitophorous vacuole membrane (PVM). The PVM forms from the host plasma membrane during invasion and is maintained by parasite effectors. Interferon-inducible GTPases (IIGs) are central in parasite clearance, however, the precise mechanism linking IIG attack of the PVM, parasite killing and inflammatory host cell death is not clear. To identify host and parasite proteins recruited to the PVM, we used Automated Spatially Targeted Optical Micro Proteomics (AutoSTOMP), a novel discovery technique that uses a confocal microscope to visualize and photo-label proteins for identification by LC-MS. Using IFNγ to induce IIG attack of the PVM and the TLR2 ligand Pam3CSK4 to upregulate inflammasome components we examined protein recruitment to the PVM in BMDCs. AutoSTOMP identified over 300 proteins differentially enriched near the PVM of unprimed, TLR2, IFNγ and IFNγ+TLR2 treated BMDCs. To identify candidate regulators of parasite clearance, we selectively purified proteins on the PVMs coated with IIG protein GBP2. We identified the inflammasome components caspase-1 and ASC as well as the apoptotic caspases-3 and -6 on GBP2-coated PVM. This was consistent with the observation that IFNγ priming was sufficient for host cell death and parasite restriction. BMDC death was partially dependent on the Aim2, ASC, Caspase1/11 and gasdermin D, however, blocking the inflammasome didn’t impair parasite restriction. By contrast, iNOS inhibitor, was sufficient to partially rescue parasite growth. In summary, we report a new tool to study the PVM proteome and identify regulators of parasite clearance and host cell death.

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Tarhoni, I., C. Fhied, J. A. Borgia, M. J. Fidler, M. Batus y P. Bonomi. "Novel Autoantibodies Biomarkers Panel to Prognosticate the Clinical Outcomes in Advanced-stage NSCLC Patients Receiving Anti PD-1/PD-L1 Immunotherapy". American Journal of Clinical Pathology 154, Supplement_1 (octubre de 2020): S142. http://dx.doi.org/10.1093/ajcp/aqaa161.311.

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Abstract Introduction/Objective Lung cancer is the leading cause of cancer-related deaths worldwide, with a majority of cases detected at a non-resectable advanced stage. Current anti PD-1/-L1 therapy has reformed cancer treatment strategies with remarkable clinical outcomes in non-small cell lung cancer (NSCLC). However, the overall response rate is still marginal, demonstrating the need for biomarkers predictive of response. The objective of this study is to develop a serum based panel to prognosticate clinical response in advanced NSCLC patients receiving anti PD-1/-L1 therapy. Methods Pooled sera from two response groups (Poor response, n=20, overall survival < 12 months; Good response, n=20, overall survival > 12 months) were evaluated via the HuProt™ Human Proteome Microarray (CDI laboratories, Baltimore, MD) to identify expressed neoantigens. Recombinant proteins representative to identified neoantigens along with their corresponding antibodies, were commercially acquired to develop a robust 13-plex bead- based immunoassay to evaluate the autoantibodies in pretreatment sera from 125 advanced-stage NSCLC patients. Finally, levels of autoantibodies were correlated to clinical outcome, including progression free survival (PFS), overall survival (OS) and grade III adverse events. Results Low baseline levels of ZNF695, MCM4, PRMT2, FGD3, GTF2A1, GLUL, CDCA3, ZNF277, GARS, GBP2, UBL7, and ASNA1 autoantibodies were found to be associated with a longer PFS (all p-values < 0.01), whereas increased levels were associated with a poor PFS outcome (0.06, HR=0.66, 95% CI). Low levels of ZNF695, MCM4, PRMT2, FGD3, GARS, GBP2, and UBL7 autoantibodies were associated with favorable OS (all p-values < 0.01). Conclusion In this study we demonstrated that serum autoantibodies have great promise to serve as a prognostic tool for immunotherapy response. We successfully developed a high performance multiplexed serum based assay to evaluate autoantibodies in an advanced NSCLC patients receiving anti PD-1/-L1 therapy.

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Mori, Gentaro, Hodaka Sasaki, Yasushi Makabe, Masao Yoshinari y Yasutomo Yajima. "The genes Scgb1a1, Lpo and Gbp2 characteristically expressed in peri-implant epithelium of rats". Clinical Oral Implants Research 27, n.º 12 (10 de abril de 2015): e190-e198. http://dx.doi.org/10.1111/clr.12601.

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Roy, Sayantan, Bing Wang, Yuan Tian y Qian Yin. "Structural and biochemical characterization of an interferon-inducible GTPase, human guanylate binding protein 2 (GBP2)". Acta Crystallographica Section A Foundations and Advances 78, a1 (29 de julio de 2022): a36. http://dx.doi.org/10.1107/s2053273322099636.

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Rahvar, Farzaneh, Mahdieh Salimi y Hossein Mozdarani. "Study of GBP2 Gene Expression and Its Promoter Methylation Pattern in Tumors of Breast Cancer Patients". Multidisciplinary Cancer Investigation 1, Supplementary 1 (1 de noviembre de 2017): 0. http://dx.doi.org/10.21859/mci-supp-04.

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Zhang, Gui-Min, Li Zheng, Hua He, Cheng-Chuang Song, Zi-Jing Zhang, Xiu-Kai Cao, Chu-Zhao Lei et al. "Associations of GBP2 gene copy number variations with growth traits and transcriptional expression in Chinese cattle". Gene 647 (marzo de 2018): 101–6. http://dx.doi.org/10.1016/j.gene.2018.01.004.

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Xie, Yihu, Christopher L. Lord, Bradley P. Clarke, Austin L. Ivey, Pate S. Hill, W. Hayes McDonald, Susan R. Wente y Yi Ren. "Structure and activation mechanism of the yeast RNA Pol II CTD kinase CTDK-1 complex". Proceedings of the National Academy of Sciences 118, n.º 3 (11 de enero de 2021): e2019163118. http://dx.doi.org/10.1073/pnas.2019163118.

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The C-terminal domain (CTD) kinase I (CTDK-1) complex is the primary RNA Polymerase II (Pol II) CTD Ser2 kinase in budding yeast. CTDK-1 consists of a cyclin-dependent kinase (CDK) Ctk1, a cyclin Ctk2, and a unique subunit Ctk3 required for CTDK-1 activity. Here, we present a crystal structure of CTDK-1 at 1.85-Å resolution. The structure reveals that, compared to the canonical two-component CDK-cyclin system, the third component Ctk3 of CTDK-1 plays a critical role in Ctk1 activation by stabilizing a key element of CDK regulation, the T-loop, in an active conformation. In addition, Ctk3 contributes to the assembly of CTDK-1 through extensive interactions with both Ctk1 and Ctk2. We also demonstrate that CTDK-1 physically and genetically interacts with the serine/arginine-like protein Gbp2. Together, the data in our work reveal a regulatory mechanism of CDK complexes.

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Wan, Jin-Yi, Wei-Hua Huang, Wei Zheng, Chan Woong Park, Su Hwan Kim, Dae Bang Seo, Kwang-Soon Shin et al. "Multiple Effects of Ginseng Berry Polysaccharides: Plasma Cholesterol Level Reduction and Enteric Neoplasm Prevention". American Journal of Chinese Medicine 45, n.º 06 (enero de 2017): 1293–307. http://dx.doi.org/10.1142/s0192415x17500719.

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The root of Asian ginseng (Panax ginseng C.A. Meyer) has been used for centuries in Oriental medicine to improve general well-being and to relieve various medical conditions. It is commonly understood that ginsenosides are responsible for the pharmacological activities of ginseng. Compared to the root of ginseng, studies on the berry are considerably limited. In this study, we evaluated the effects of polysaccharides from Asian ginseng berries on plasma lipid levels, chemically-induced enteric inflammation and neoplasm, and cancer chemoprevention in different experimental models. We tested two polysaccharide preparations: regular ginseng berry polysaccharide extract (GBPE) and ginseng berry polysaccharide portion (GBPP, removed MV [Formula: see text]). We first observed that both oral GBPE and oral GBPP significantly reduced plasma cholesterol and triglycerides levels in a dose-related manner in ob/ob mice, without obvious body weight changes. Then, in AOM/DSS-induced acute colitis mice, GBPE and GBPP significantly ameliorated the increased gut disease activity index and inhibited the reduction of the colon length. Further, the berry polysaccharides significantly suppressed chemically-induced pro-inflammatory cytokine levels. This is consistent with the observation that GBPE and GBPP attenuated tumorigenesis in mice by significantly and dose-dependently reducing tumor load. Finally, in vitro HCT-116 and HT-29 human colon cancer cells were used. While these berry preparations had better antiproliferation effects on the HCT-116 than the HT-29 cells, the GBPE had significantly stronger inhibitory effects than GBPP. The observed in vitro GBPE’s effect could contribute to the actions of its small-molecule non-polysaccharide compounds due to their direct antiproliferative activities. Results obtained from the present study suggest that ginseng berry polysaccharides may have a therapeutic role in the management of high lipid levels, enteric inflammation, and colon malignancies.

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Miao, Qi, Meihong Ge y Lili Huang. "Up-regulation of GBP2 is Associated with Neuronal Apoptosis in Rat Brain Cortex Following Traumatic Brain Injury". Neurochemical Research 42, n.º 5 (27 de febrero de 2017): 1515–23. http://dx.doi.org/10.1007/s11064-017-2208-x.

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Traver, Maria K., Stanley C. Henry, Viviana Cantillana, Tim Oliver, Julia P. Hunn, Jonathan C. Howard, Sandra Beer, Klaus Pfeffer, Jörn Coers y Gregory A. Taylor. "Immunity-related GTPase M (IRGM) proteins influence the localization of guanylate-binding protein 2 (GBP2) by modulating macroautophagy." Journal of Biological Chemistry 288, n.º 16 (19 de abril de 2013): 11504. http://dx.doi.org/10.1074/jbc.a111.251967.

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Traver, Maria K., Stanley C. Henry, Viviana Cantillana, Tim Oliver, Julia P. Hunn, Jonathan C. Howard, Sandra Beer, Klaus Pfeffer, Jörn Coers y Gregory A. Taylor. "Immunity-related GTPase M (IRGM) Proteins Influence the Localization of Guanylate-binding Protein 2 (GBP2) by Modulating Macroautophagy". Journal of Biological Chemistry 286, n.º 35 (12 de julio de 2011): 30471–80. http://dx.doi.org/10.1074/jbc.m111.251967.

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Meng, Kun, Yu-Ying Li, Dan-Ya Liu, Li-Ling Hu, Yun-Long Pan, Chris Zhiyi Zhang y Qing-Yu He. "A five-protein prognostic signature with GBP2 functioning in immune cell infiltration of clear cell renal cell carcinoma". Computational and Structural Biotechnology Journal 21 (2023): 2621–30. http://dx.doi.org/10.1016/j.csbj.2023.04.015.

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Li, Ming y Clark Chen. "DDDR-16. GBP3-STING INTERACTION IN GLIOBLASTOMA COORDINATES AUTOPHAGY, ANTI-OXIDATIVE, AND DNA REPAIR PROGRAMS IN RESPONSE TO TEMOZOLOMIDE". Neuro-Oncology 24, Supplement_7 (1 de noviembre de 2022): vii102. http://dx.doi.org/10.1093/neuonc/noac209.381.

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Abstract INTRODUCTION Guanylate-binding proteins (GBPs) are a group of dynamin-related large (~65 kDa) GTPases expressed in response to interferon and mediate intracellular immunity. In contrast to the Ras- or Rho family of small GTPases (~20 kDa) or the trimeric GTPases, little is known about the function of GBPs beyond their role in innate cellular immunity. METHODS Informatic analysis of clinically annotated glioblastoma datasets, laboratory studies of protein-protein interaction, functional characterization after depletion or exogenous expression RESULTS Of the seven known members of human GBPs, only GBP3 showed significant up-regulation in response to temozolomide, the standard-of-care DNA-alkylating chemotherapy for glioblastoma. Importantly, high levels of glioblastoma GBP3 expression was associated with worsened survival after temozolomide treatment. Consistent with this observation, exogenous expression of GBP3 induced temozolomide resistance in independent patient-derived glioblastoma neurosphere lines, while GBP3 silencing conferred temozolomide sensitivity, both in vitro and in vivo. This sensitivity was associated with the accumulation of cytoplasmic DNA fragments, suggesting the involvement of STING. Supporting this hypothesis, the N-terminal of GBP3 physically interacted with STING to prevent proteasome-mediated degradation of STING. Since cytoplasmic DNA bound STING activates key transcriptional programs, we profiled transcription programs requiring both GBP3 and STING expression and identified an autophagy program mediated by p62 (autophagy), a defense program against oxidative insults mediated by nuclear factor erythroid 2 like 2 (NFE2L2, NRF2), and a DNA repair program mediated by O6-methylguanine-DNA-methyltransferase (MGMT). These programs were previously shown to play central roles in cellular resistance to DNA alkylating agents. CONCLUSION In addition to its central role in innate immunity, GBP3 mediates cellular response to DNA damage through coordination of autophagy, anti-oxidative, and DNA repair programs.

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Bosgraaf, Leonard, Henk Russcher, Helena Snippe, Sonya Bader, Joyce Wind y Peter J. M. Van Haastert. "Identification and Characterization of Two Unusual cGMP-stimulated Phoshodiesterases in Dictyostelium". Molecular Biology of the Cell 13, n.º 11 (noviembre de 2002): 3878–89. http://dx.doi.org/10.1091/mbc.e02-05-0302.

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Recently, we recognized two genes, gbpA andgbpB, encoding putative cGMP-binding proteins with a Zn2+-hydrolase domain and two cyclic nucleotide binding domains. The Zn2+-hydrolase domains belong to the superfamily of β-lactamases, also harboring a small family of class II phosphodiesterases from bacteria and lower eukaryotes. Gene inactivation and overexpression studies demonstrate thatgbpA encodes the cGMP-stimulated cGMP-phosphodiesterase that was characterized biochemically previously and was shown to be involved in chemotaxis. cAMP neither activates nor is a substrate of GbpA. The gbpB gene is expressed mainly in the multicellular stage and seems to encode a dual specificity phosphodiesterase with preference for cAMP. The enzyme hydrolyses cAMP ∼9-fold faster than cGMP and is activated by cAMP and cGMP with aK A value of ∼0.7 and 2.3 μM, respectively. Cells with a deletion of the gbpB gene have increased basal and receptor stimulated cAMP levels and are sporogeneous. We propose that GbpA and GbpB hydrolyze the substrate in the Zn2+-hydrolase domain, whereas the cyclic nucleotide binding domains mediate activation. The human cGMP-stimulated cAMP/cGMP phosphodiesterase has similar biochemical properties, but a completely different topology: hydrolysis takes place by a class I catalytic domain and GAF domains mediate cGMP activation.

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Ramsauer, K., M. Farlik, G. Zupkovitz, C. Seiser, A. Kroger, H. Hauser y T. Decker. "Distinct modes of action applied by transcription factors STAT1 and IRF1 to initiate transcription of the IFN- -inducible gbp2 gene". Proceedings of the National Academy of Sciences 104, n.º 8 (9 de febrero de 2007): 2849–54. http://dx.doi.org/10.1073/pnas.0610944104.

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Hurt, Ed, Ming-juan Luo, Susanne Röther, Robin Reed y Katja Sträßer. "Cotranscriptional recruitment of the serine-arginine-rich (SR)-like proteins Gbp2 and Hrb1 to nascent mRNA via the TREX complex". Proceedings of the National Academy of Sciences 101, n.º 7 (9 de febrero de 2004): 1858–62. http://dx.doi.org/10.1073/pnas.0308663100.

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Li, Ming y Clark Chen. "CSIG-03. GBP5 DRIVES MALIGNANCY OF GLIOBLASTOMA". Neuro-Oncology 23, Supplement_6 (2 de noviembre de 2021): vi33. http://dx.doi.org/10.1093/neuonc/noab196.129.

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Abstract Guanylate binding proteins (GBPs), a family of interferon-inducible large GTPase, play a pivotal role in cell-autonomous immunity and tumor malignant transformation. Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor in adults. Here we show that GBP5 was highly expressed in GBM cell lines and in clinical samples, especially in the mesenchymal subtype. The expression levels of GBP5 were negatively correlated with the prognosis of GBM patients. Overexpression of GBP5 promoted the proliferation, migration, and invasion of GBM cells in vitro and in vivo. In contrast, silencing GBP5 by RNA interference exhibited the opposite effects. Consequently, targeting GBP5 in GBM cells resulted in impaired tumor growth and prolonged survival time of mice with GBM tumors. We further identified that the Src/ERK1/2/MMP3 axis was essential for GBP5-promoted GBM aggressiveness. These findings suggest that GBP5 may represent a novel target for GBM intervention.

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Windgassen, Merle y Heike Krebber. "Identification of Gbp2 as a novel poly(A) + RNA‐binding protein involved in the cytoplasmic delivery of messenger RNAs in yeast". EMBO reports 4, n.º 3 (14 de febrero de 2003): 278–83. http://dx.doi.org/10.1038/sj.embor.embor763.

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Godoy, Patricio, Cristina Cadenas, Birte Hellwig, Rosemarie Marchan, Joanna Stewart, Raymond Reif, Miriam Lohr et al. "Interferon-inducible guanylate binding protein (GBP2) is associated with better prognosis in breast cancer and indicates an efficient T cell response". Breast Cancer 21, n.º 4 (22 de septiembre de 2012): 491–99. http://dx.doi.org/10.1007/s12282-012-0404-8.

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Wang, Guanghui, Peng Sun, Zhongjuan Sun, Jindong Zhu, Dan Yu, Zhe Tang, Zonghua Wang, Chenfang Wang y Huawei Zheng. "Sgh1, an SR-like Protein, Is Involved in Fungal Development, Plant Infection, and Pre-mRNA Processing in Fusarium graminearum". Journal of Fungi 8, n.º 10 (8 de octubre de 2022): 1056. http://dx.doi.org/10.3390/jof8101056.

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Serine/arginine (SR) proteins are essential pre-mRNA splicing factors in eukaryotic organisms. Our previous studies have shownthat the unique SR-specific protein kinase Srk1 is important for RNA splicing and gene transcription in Fusarium graminearum, and interacts with two SR proteins, FgSrp1 and FgSrp2. In this study, we have identified an SR-like protein called Sgh1 in F. graminearum, which is orthologous to budding yeast paralogous Gbp2 and Hrb1. Our data have shownthat the Sgh1 is involved in vegetative growth, conidiation, sexual reproduction, DON synthesis, and plant infection. Moreover, the Sgh1 is mainly localized to the nucleus. RNA-seq analysis has shownthat the expression of over 1100 genes and the splicing efficiency in over 300 introns were affected in theΔsgh1 mutant. Although the RS domain and all three of the RRM domains are important for the Sgh1 functions, only the RS domain is responsible for its nuclear localization. Finally, we verified that the Sgh1 interacts with the unique SR-specific kinase Srk1 in F. graminearum by the yeast-two hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. Taken together, our results have revealed that the Sgh1 regulates the fungal development, plant infection, and the pre-mRNA processing, and the RS domain regulates the function of the Sgh1 by modulating its nucleocytoplasmic shuttling.

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Puxeddu, E., J. A. Knauf, M. A. Sartor, N. Mitsutake, E. P. Smith, M. Medvedovic, C. R. Tomlinson, S. Moretti y J. A. Fagin. "RET/PTC-induced gene expression in thyroid PCCL3 cells reveals early activation of genes involved in regulation of the immune response". Endocrine-Related Cancer 12, n.º 2 (junio de 2005): 319–34. http://dx.doi.org/10.1677/erc.1.00947.

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RET/PTC rearrangements represent key genetic events involved in papillary thyroid carcinoma (PTC) initiation. The aim of the present study was to identify the early changes in gene expression induced by RET/PTC in thyroid cells. For this purpose, microarray analysis was conducted on PCCL3 cells conditionally expressing the RET/PTC3 oncogene. Gene expression profiling 48 h after activation of RET/PTC3 identified a statistically significant modification of expression of 270 genes. Quantitative PCR confirmation of 20 of these demonstrated 90% accuracy of the microarray. Functional clustering of genes with greater than or less than 1.75-fold expression change (86 genes) revealed RET/PTC3-induced regulation of genes with key functions in apoptosis (Ripk3, Tdga), cell–cell signaling (Cdh6, Fn1), cell cycle (Il24), immune and inflammation response (Cxcl10, Scya2, Il6, Gbp2, Oas1, Tap1, RT1Aw2, C2ta, Irf1, Lmp2, Psme2, Prkr), metabolism (Aldob, Ptges, Nd2, Gss, Gstt1), signal transduction (Socs3, Nf1, Jak2, Cpg21, Dusp6, Socs1, Stat1, Stat3, Cish) and transcription (Nr4a1, Junb, Hfh1, Runx1, Foxe1). Genes coding for proteins involved in the immune response and in intracellular signal transduction pathways activated by cytokines and chemokines were strongly represented, indicating a critical role of RET/PTC3 in the early modulation of the immune response.

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Rigolet, Muriel, Cyrielle Hou, Yasmine Baba Amer, Jessie Aouizerate, Baptiste Periou, Romain K. Gherardi, Peggy Lafuste y François Jérôme Authier. "Distinct interferon signatures stratify inflammatory and dysimmune myopathies". RMD Open 5, n.º 1 (febrero de 2019): e000811. http://dx.doi.org/10.1136/rmdopen-2018-000811.

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ObjectiveThe role of interferons (IFN) in the pathophysiology of primary inflammatory and dysimmune myopathies (IDM) is increasingly investigated, notably because specific neutralisation approaches may constitute promising therapeutic tracks. In present work we analysed the muscular expression of specific IFNα/β and IFNγ-stimulated genes in patients with various types of IDM.Methods39 patients with IDM with inclusion body myositis (IBM, n=9), dermatomyositis (DM, n=10), necrotising autoimmune myopathies (NAM, n=10) and antisynthetase myositis (ASM, n=10), and 10 controls were included. Quantification of expression levels of IFNγ, ISG15, an IFNα/β-inducible gene and of six IFNγ-inducible genes (GBP2, HLA-DOB, HLA-DPB, CIITA, HLA-DRB and HLA-DMB) was performed on muscle biopsy samples.ResultsDM usually associated with strong type I IFNα/β signature, IBM and ASM with prominent type II IFNγ signature and NAM with neither type I nor type II IFN signature. Immunofluorescence study in ASM and IBM showed myofibre expression of major histocompatibility class 2 (MHC-2) and CIITA, confirming the induction of the IFNγ pathway. Furthermore, MHC-2-positive myofibres were observed in close proximity to CD8+ T cells which produce high levels of IFNγ.ConclusionDistinct IFN signatures allow a more distinct segregation of IDMs and myofibre MHC-2 expression is a reliable biomarker of type II IFN signature.

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Zupkovitz, Gordin, Julia Tischler, Markus Posch, Iwona Sadzak, Katrin Ramsauer, Gerda Egger, Reinhard Grausenburger et al. "Negative and Positive Regulation of Gene Expression by Mouse Histone Deacetylase1". Molecular and Cellular Biology 26, n.º 21 (28 de agosto de 2006): 7913–28. http://dx.doi.org/10.1128/mcb.01220-06.

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ABSTRACT Histone deacetylases (HDACs) catalyze the removal of acetyl groups from core histones. Because of their capacity to induce local condensation of chromatin, HDACs are generally considered repressors of transcription. In this report, we analyzed the role of the class I histone deacetylase HDAC1 as a transcriptional regulator by comparing the expression profiles of wild-type and HDAC1-deficient embryonic stem cells. A specific subset of mouse genes (7%) was deregulated in the absence of HDAC1. We identified several putative tumor suppressors (JunB, Prss11, and Plagl1) and imprinted genes (Igf2, H19, and p57) as novel HDAC1 targets. The majority of HDAC1 target genes showed reduced expression accompanied by recruitment of HDAC1 and local reduction in histone acetylation at regulatory regions. At some target genes, the related deacetylase HDAC2 partially masks the loss of HDAC1. A second group of genes was found to be downregulated in HDAC1-deficient cells, predominantly by additional recruitment of HDAC2 in the absence of HDAC1. Finally, a small set of genes (Gja1, Irf1, and Gbp2) was found to require HDAC activity and recruitment of HDAC1 for their transcriptional activation. Our study reveals a regulatory cross talk between HDAC1 and HDAC2 and a novel function for HDAC1 as a transcriptional coactivator.

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Feng, Jian, Zhongying Cao, Li Wang, Yushun Wan, Nanfang Peng, Qing Wang, Xueyuan Chen, Yaqin Zhou y Ying Zhu. "Inducible GBP5 Mediates the Antiviral Response via Interferon-Related Pathways during Influenza A Virus Infection". Journal of Innate Immunity 9, n.º 4 (2017): 419–35. http://dx.doi.org/10.1159/000460294.

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Guanylate binding protein (GBP) 5 belongs to the GBP family, which is involved in important cellular processes, including signal transduction, translation, vesicle trafficking, and exocytosis. Structurally, GBPs display a high degree of homology and share highly conserved GTP-binding or hydrolysis domains. GBP5 was reported to be a critical cellular factor in inflammasome assembly. However, little is known about its role in the host antiviral innate immune response. In this study, we found that GBP5 expression was significantly elevated in influenza patients and influenza A virus-infected A549 human lung epithelial cells. The overexpression of GBP5 inhibited virus replication by enhancing the expression of virus-induced interferon (IFN) and IFN-related effectors. Knockdown of GBP5 had the opposite effect. Moreover, GBP5 enhanced endogenous IFN expression by interacting with the NF-κB-essential modulator complex and stimulating NF-κB signaling. Additionally, the expression of proinflammatory factors, such as IL-6, IL-8, tumor necrosis factor-α, cyclooxygenase-2, and inducible nitric oxide synthase, was also activated by GBP5. Taken together, our results reveal that GBP5 inhibited virus replication through the activation of IFN signaling and proinflammatory factors.

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Jiang, Tongmeng, Pan Jin, Guoxiu Huang y Shi-Cheng Li. "The function of guanylate binding protein 3 (GBP3) in human cancers by pan-cancer bioinformatics". Mathematical Biosciences and Engineering 20, n.º 5 (2023): 9511–29. http://dx.doi.org/10.3934/mbe.2023418.

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<abstract> <p>As a guanylate binding protein (GBPs) member, GBP3 is immune-associated and may participate in oncogenesis and cancer therapy. Since little has been reported on GBP3 in this field, we provide pan-cancer bioinformatics to investigate the role of GBP3 in human cancers. The GBP3 expression, related clinical outcomes, immune infiltrates, potential mechanisms and mutations were conducted using tools including TIMER2.0, GEPIA2.0, SRING, DAVID and cBioPortal. Results showed an increased risk of high GBP3 in Brain Lower Grade Glioma (LGG) and Lung Squamous Cell Carcinoma (LUSC) and a decreased risk of GBP3 in Sarcoma (SARC) and Skin Cutaneous Melanoma (SKCM) (p ≤ 0.05). GBP3 was negatively correlated with CAFs in Esophageal Adenocarcinoma (ESCA) and positively correlated with CAFs in LGG, LUSC and TGCG (p ≤ 0.05). In addition, GBP3 was positively correlated with CD8+ T cells in Bladder Urothelial Carcinoma (BLCA), Cervical Squamous Cell Carcinoma (CESC), Kidney Renal Clear Cell Carcinoma (KIRC), SARC, SKCM, SKCM-Metastasis and Uveal Melanoma (UVM) (p ≤ 0.05). Potentially, GBP3 may participate in the homeostasis between immune and adaptive immunity in cancers. Moreover, the most frequent mutation sites of GBP3 in cancers are R151Q/<sup>*</sup> and K380N. This study would provide new insight into cancer prognosis and therapy.</p> </abstract>

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Cheng, Shun-Wen, Po-Chih Chen, Tzong-Rong Ger, Hui-Wen Chiu y Yuan-Feng Lin. "GBP5 Serves as a Potential Marker to Predict a Favorable Response in Triple-Negative Breast Cancer Patients Receiving a Taxane-Based Chemotherapy". Journal of Personalized Medicine 11, n.º 3 (12 de marzo de 2021): 197. http://dx.doi.org/10.3390/jpm11030197.

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Pre-operative (neoadjuvant) or post-operative (adjuvant) taxane-based chemotherapy is still commonly used to treat patients with triple-negative breast cancer (TNBC). However, there are still no effective biomarkers used to predict the responsiveness and efficacy of taxane-based chemotherapy in TNBC patients. Here we find that guanylate-binding protein 5 (GBP5), compared to other GBPs, exhibits the strongest prognostic significance in predicting TNBC recurrence and progression. Whereas GBP5 upregulation showed no prognostic significance in non-TNBC patients, a higher GBP5 level predicted a favorable recurrence and progression-free condition in the TNBC cohort. Moreover, we found that GBP5 expression negatively correlated with the 50% inhibitory concentration (IC50) of paclitaxel in a panel of TNBC cell lines. The gene knockdown of GBP5 increased the IC50 of paclitaxel in the tested TNBC cells. In TNBC patients receiving neoadjuvant or adjuvant chemotherapy, a higher GBP5 level strongly predicted a good responsiveness. Computational simulation by the Gene Set Enrichment Analysis program and cell-based assays demonstrated that GBP5 probably enhances the cytotoxic effectiveness of paclitaxel via activating the Akt/mTOR signaling axis and suppressing autophagy formation in TNBC cells. These findings suggest that GBP5 could be a good biomarker to predict a favorable outcome in TNBC patients who decide to receive a taxane-based neoadjuvant or adjuvant therapy.

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Duque, Cristiane, Rafael N. Stipp, Bing Wang, Daniel J. Smith, José F. Höfling, Howard K. Kuramitsu, Margaret J. Duncan y Renata O. Mattos-Graner. "Downregulation of GbpB, a Component of the VicRK Regulon, Affects Biofilm Formation and Cell Surface Characteristics ofStreptococcus mutans". Infection and Immunity 79, n.º 2 (15 de noviembre de 2010): 786–96. http://dx.doi.org/10.1128/iai.00725-10.

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ABSTRACTThe virulence of the dental caries pathogenStreptococcus mutansrelies in part on the sucrose-dependent synthesis of and interaction with glucan, a major component of the extracellular matrix of tooth biofilms. However, the mechanisms by which secreted and/or cell-associated glucan-binding proteins (Gbps) produced byS. mutansparticipate in biofilm growth remain to be elucidated. In this study, we further investigate GbpB, an essential immunodominant protein with similarity to murein hydrolases. A conditional knockdown mutant that expressedgbpBantisense RNA under the control of a tetracycline-inducible promoter was constructed in strain UA159 (UACA2) and used to investigate the effects of GbpB depletion on biofilm formation and cell surface-associated characteristics. Additionally, regulation ofgbpBby the two-component system VicRK was investigated, and phenotypic analysis of avicKmutant (UAvicK) was performed. GbpB was directly regulated by VicR, and several phenotypic changes were comparable between UACA2 and UAvicK, although differences between these strains existed. It was established that GbpB depletion impaired initial phases of sucrose-dependent biofilm formation, while exogenous native GbpB partially restored the biofilm phenotype. Several cellular traits were significantly affected by GbpB depletion, including altered cell shape, decreased autolysis, increased cell hydrophobicity, and sensitivity to antibiotics and osmotic and oxidative stresses. These data provide the first experimental evidence for GbpB participation in sucrose-dependent biofilm formation and in cell surface properties.

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48

Pradipta, Ariel, Miwa Sasai, Kou Motani, Ji Su Ma, Youngae Lee, Hidetaka Kosako y Masahiro Yamamoto. "Cell-autonomous Toxoplasma killing program requires Irgm2 but not its microbe vacuolar localization". Life Science Alliance 4, n.º 7 (2 de junio de 2021): e202000960. http://dx.doi.org/10.26508/lsa.202000960.

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Interferon-inducible GTPases, such as immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs), are essential for cell-autonomous immunity against a wide variety of intracellular pathogens including Toxoplasma. IRGs comprise regulatory and effector subfamily proteins. Regulatory IRGs Irgm1 and Irgm3 play important roles in anti-Toxoplasma immunity by globally controlling effector IRGs and GBPs. There is a remaining regulatory IRG, called Irgm2, which highly accumulates on parasitophorous vacuole membranes (PVMs). Very little is known about the mechanism of the unique localization on Toxoplasma PVMs. Here, we show that Irgm2 is important to control parasite killing through recruitment of Gbp1 and Irgb6, which does not require Irgm2 localization at Toxoplasma PVMs. Ubiquitination of Irgm2 in the cytosol, but not at the PVM, is also important for parasite killing through recruitment of Gbp1 to the PVM. Conversely, PVM ubiquitination and p62/Sqstm1 loading at later time points post-Toxoplasma infection require Irgm2 localization at the PVM. Irgm2-deficient mice are highly susceptible to Toxoplasma infection. Taken together, these data indicate that Irgm2 selectively controls accumulation of anti-Toxoplasma effectors to the vacuole in a manner dependent or independent on Irgm2 localization at the Toxoplasma PVM, which mediates parasite killing.

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49

Côrte-Real, João Vasco, Hanna-Mari Baldauf, José Melo-Ferreira, Joana Abrantes y Pedro José Esteves. "Evolution of Guanylate Binding Protein (GBP) Genes in Muroid Rodents (Muridae and Cricetidae) Reveals an Outstanding Pattern of Gain and Loss". Frontiers in Immunology 13 (9 de febrero de 2022). http://dx.doi.org/10.3389/fimmu.2022.752186.

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Guanylate binding proteins (GBPs) are paramount in the host immunity by providing defense against invading pathogens. Multigene families related to the immune system usually show that the duplicated genes can either undergo deletion, gain new functions, or become non-functional. Here, we show that in muroids, the Gbp genes followed an unusual pattern of gain and loss of genes. Muroids present a high diversity and plasticity regarding Gbp synteny, with most species presenting two Gbp gene clusters. The phylogenetic analyses revealed seven different Gbps groups. Three of them clustered with GBP2, GBP5 and GBP6 of primates. Four new Gbp genes that appear to be exclusive to muroids were identified as Gbpa, b, c and d. A duplication event occurred in the Gbpa group in the common ancestor of Muridae and Cricetidae (~20 Mya), but both copies were deleted from the genome of Mus musculus, M. caroli and Cricetulus griseus. The Gbpb gene emerged in the ancestor of Muridae and Cricetidae and evolved independently originating Gbpb1 in Muridae, Gbpb2 and Gbpb3 in Cricetidae. Since Gbpc appears only in three species, we hypothesize that it was present in the common ancestor and deleted from most muroid genomes. The second Gbp gene cluster, Gbp6, is widespread across all muroids, indicating that this cluster emerged before the Muridae and Cricetidae radiation. An expansion of Gbp6 occurred in M. musculus and M. caroli probably to compensate the loss of Gbpa and b. Gbpd is divided in three groups and is present in most muroids suggesting that a duplication event occurred in the common ancestor of Muridae and Cricetidae. However, in Grammomys surdaster and Mus caroli, Gbpd2 is absent, and in Arvicanthis niloticus, Gbpd1 appears to have been deleted. Our results further demonstrated that primate GBP1, GBP3 and GBP7 are absent from the genome of muroids and showed that the Gbp gene annotations in muroids were incorrect. We propose a new classification based on the phylogenetic analyses and the divergence between the groups. Extrapolations to humans based on functional studies of muroid Gbps should be re-evaluated. The evolutionary analyses of muroid Gbp genes provided new insights about the evolution and function of these genes.

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50

Place, David E., R. K. Subbarao Malireddi, Jieun Kim, Peter Vogel, Masahiro Yamamoto y Thirumala-Devi Kanneganti. "Osteoclast fusion and bone loss are restricted by interferon inducible guanylate binding proteins". Nature Communications 12, n.º 1 (21 de enero de 2021). http://dx.doi.org/10.1038/s41467-020-20807-8.

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AbstractChronic inflammation during many diseases is associated with bone loss. While interferons (IFNs) are often inhibitory to osteoclast formation, the complex role that IFN and interferon-stimulated genes (ISGs) play in osteoimmunology during inflammatory diseases is still poorly understood. We show that mice deficient in IFN signaling components including IFN alpha and beta receptor 1 (IFNAR1), interferon regulatory factor 1 (IRF1), IRF9, and STAT1 each have reduced bone density and increased osteoclastogenesis compared to wild type mice. The IFN-inducible guanylate-binding proteins (GBPs) on mouse chromosome 3 (GBP1, GBP2, GBP3, GBP5, GBP7) are required to negatively regulate age-associated bone loss and osteoclastogenesis. Mechanistically, GBP2 and GBP5 both negatively regulate in vitro osteoclast differentiation, and loss of GBP5, but not GBP2, results in greater age-associated bone loss in mice. Moreover, mice deficient in GBP5 or chromosome 3 GBPs have greater LPS-mediated inflammatory bone loss compared to wild type mice. Overall, we find that GBP5 contributes to restricting age-associated and inflammation-induced bone loss by negatively regulating osteoclastogenesis.

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