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: 7882665
• 负责人: KERRI A MOWEN
• 金额: $ 37.52万
• 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/7882665
• 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 信号通路的参与介导其抗病毒、抗增殖和免疫调节作用。IFN(/( 受体的连接导致 Jak 酪氨酸的激活) Stat1 的激酶和随后的酪氨酸磷酸化要么形成同二聚体，要么通过互惠的 SH2 结构域与 Stat2 形成异二聚体。然后，二聚化的 Stats 易位到细胞核，在细胞核中与 IFN 反应基因中的调节元件结合。除了酪氨酸激酶之外，蛋白精氨酸甲基转移酶 (PRMT) 通过与 IFN(/( 信号通路中的成员) 的物理关联而参与其中。 Jak/Stat 通路和通过基因研究，丙型肝炎病毒通过靶向 Stat1 的精氨酸甲基化来干扰 IFN 信号传导。 Carm1 精氨酸甲基转移酶对 IFN(驱动的 Stat1 激活) 表现出升高的反应，包括 Stat1 去磷酸化的缺陷和。此外，在体外测定中，Carm1 可以甲基化 Stat1。我们的假设是 Carm1 通过 TCPTP 促进 Stat1 去磷酸化来负向调节 Stat1 驱动的转录。具体目标： 1) 定义 Carm1 在 IFN1/2 信号通路中的交叉点。我们将检查 Stat1 DNA 结合、四聚化以及与靶基因的关联。我们还将表征 Jak1、Tyk2、Stat1、Stat2、Stat3 和 Stat5 的活性。 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Carm1对Stat1与Pias1和TCPTP相互作用的影响。将确定 Stat1 甲基化位点。 3）研究IFN(/(信号通路对Carm1的调节，包括表达、酶活性、亚细胞定位和翻译后修饰。意义。这些研究将深入了解PRMTs调节I型IFN信号传导的机制，这可能公共卫生相关性：干扰素细胞因子家族通过调节细胞增殖和抗病毒防御以及直接调节病原体来控制病原体感染。由于这些原因，干扰素在临床上用于治疗病毒和恶性疾病。我们的项目将解决干扰素信号减弱的分子机制。