The Role of Arginine Methyltransferases in Interferon Signaling

精氨酸甲基转移酶在干扰素信号转导中的作用

• 批准号: 7686734
• 负责人: KERRI A MOWEN
• 金额: $ 37.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686734
• 关键词: Address; Antimicrobial Effect; Antiviral Agents; Arginine; Attenuated; Autoimmune Diseases; Autoimmune Process; Binding; Binding Sites; Cell Nucleus; Cell Proliferation; Cells; Complex; DNA Binding; Development; Dimerization; Disease; Drosophila genus; Embryo; Event; Exhibits; Family; Fibroblasts; Gene Targeting; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Hepatitis C; Hepatitis C virus; Homologous Gene; Immune response; In Vitro; Infection; Interferon Receptor; Interferon Type I; Interferons; Kinetics; Length; Ligation; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Methylation; Molecular; Multiple Sclerosis; Mus; Nuclear; Nuclear Export; Nuclear Translocation; Pathology; Pathway interactions; Phosphotransferases; Post-Translational Protein Processing; Property; Protein Dephosphorylation; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Protein-Arginine N-Methyltransferase; Regulation; Regulatory Element; Role; Signal Pathway; Signal Transduction; Site; Systemic Lupus Erythematosus; Testing; Tyrosine; Tyrosine Phosphorylation; Viral; Virus Diseases; arginine methyltransferase; cytokine; in vitro Assay; insight; member; metaplastic cell transformation; pathogen; public health relevance; receptor; response; src Homology Region 2 Domain

DESCRIPTION (provided by applicant): The cytokine Interferon (IFN) (/( mediates its antiviral, antiproliferative, and immunomodulatory effects through the engagement of the Jak/Stat signaling pathway. Ligation of the IFN(/( receptor results in activation of Jak tyrosine kinases and subsequent tyrosine phosphorylation of Stat1. Phosphorylated Stat1 either forms homodimers or heterodimerizes with Stat2 via reciprocal SH2 domain interactions. Dimerized Stats then translocate to the nucleus where they bind to regulatory elements in IFN response genes. In addition to tyrosine kinases, protein arginine methyltransferases (PRMT) have been implicated in IFN(/( signaling pathways through their physical association with members of the Jak/Stat pathway and through genetic studies. The Hepatitis C Virus interferes with IFN signaling by targeting arginine methylation of Stat1. We have now found that cells deficient in the Carm1 arginine methyltransferase exhibited elevated responses to IFN(-driven Stat1 activation, including a deficiency in Stat1 dephosphorylation and. Furthermore, Carm1 can methylate Stat1 in in vitro assays. Our HYPOTHESIS is that Carm1 negatively regulates Stat1 driven transcription by promoting the dephosphorylation of Stat1 by TCPTP. Specific Aims: 1) Define the intersection of Carm1 within IFN1/2 signaling pathways. We will examine Stat1 DNA binding, tetramerization, and association with target genes. We will also characterize the activity of Jak1, Tyk2, Stat1, Stat2, Stat3, and Stat5. 2) Determine the mechanism by which Carm1 regulates Stat1 dephosphorylation, including examining the importance of Carm1 catalytic activity and the effects on Carm1 on Stat1 interaction with Pias1 and TCPTP. The Stat1 methylation site will be determined. 3) Investigate the regulation of Carm1 by the IFN(/( signaling pathway, including expression, enzymatic activity, subcellular localization, and posttranslational modifications. Significance. These studies will provide insight into the mechanisms by which PRMTs regulate Type I IFN signaling, which may be altered during viral infection. PUBLIC HEALTH RELEVANCE: The interferon family of cytokines control pathogen infections through regulation of cellular proliferation and antiviral defenses, as well as through direct modulation of the immune response. For these reasons, the interferons are used clinically to treat viral and malignant diseases. Our project will address the molecular mechanisms of by which interferon signals are attenuated.

描述（由申请人提供）：细胞因子干扰素（IFN）（/（（通过JAK/Stat STAT信号通路的参与，介导其抗病毒，抗增殖和免疫调节作用与互惠的SH2域相互作用与STAT2相互作用。通过靶向STAT1的精氨酸甲基化来干扰IFN信号。此外，CARM1可以在体外测定中甲基化STAT1。我们的假设是CARM1通过促进TCPTP促进STAT1的去磷酸化来负面调节STAT1驱动的转录。具体目的：1）定义IFN1/2信号通路内CARM1的相交。我们将检查STAT1 DNA结合，四聚体和与靶基因的关联。我们还将表征JAK1，TYK2，STAT1，STAT2，STAT3和STAT5的活动。 2）确定CARM1调节STAT1去磷酸化的机制，包括检查CARM1催化活性的重要性以及对CARM1对STAT1与PIAS1和PIAS1和TCPTP相互作用的影响。将确定STAT1甲基化位点。 3）通过IFN（/（（包括表达，酶活性，亚细胞定位，亚细胞定位和翻译后修饰）调节CARM1的调节。显着性。这些研究将提供对PRMTS调节I型IFN信号的机制的见解，该机制可以通过病毒性感染而改变。抗病毒防御以及通过这些原因的直接调节。