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Role of FIP200 in RIG-I-mediated innate immunity

FIP200 在 RIG-I 介导的先天免疫中的作用

基本信息

批准号：
10295767
负责人：
Shitao Li
金额：
$ 34.2万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-15 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10295767
关键词：
Antiviral Agents Autoimmune Diseases Autophagocytosis Bioinformatics Caspase Cells Communicable Diseases Data Dimerization Double-Stranded RNA Embryo Family Fibroblasts Genes Goals Grant Host Defense Mechanism Human Immune system Innate Immune Response Interferon Activation Interferon Type I Interferons Interphase Cell Knock-out Knockout Mice Knowledge Ligands Literature Mediating Molecular Mus Natural Immunity Nucleic Acids PTK2 gene Phosphorylation Pilot Projects Production Protein Dephosphorylation Protein phosphatase Proteins Proteomics RNA RNA Virus Infections RNA Viruses Regulation Resistance Role Signal Pathway Signal Transduction Specificity Tretinoin Vesicular stomatitis Indiana virus Viral Viral Load result Virus Diseases Virus Replication base conditional knockout cytokine dimer in vivo insight macrophage monocyte mouse model novel novel therapeutic intervention prevent protein complex recruit response sensor therapy design tripolyphosphate

项目摘要

Project summary Retinoic acid-inducible gene I (RIG-I) is an intracellular sensor for recognition of viral double-stranded RNA (dsRNA) and 5` triphosphate RNA. Following RNA recognition, RIG-I induces a robust production of type I interferons (IFN). To prevent aberrant IFN expression, RIG-I activation is regulated by several steps, including dephosphorylation and oligomerization of the CARD domain of RIG-I. Phosphorylation of the CARD domain retains RIG-I inactive in the resting cells. Upon RNA ligand engagement, RIG-I is dephosphorylated by the protein phosphatase 1 (PP1), which permits subsequent oligomerization for activation. However, PP1 has numerous substrates in the cell and what determines the specificity of PP1 towards RIG-I is unknown. Furthermore, how dephosphorylation facilitates RIG-I oligomerization is not clear. Thus, there is a critical need to define the regulatory mechanisms for the dephosphorylation and oligomerization of RIG-I. Elucidation of these mechanisms will not only reveal a novel regulatory mechanism of host defense, but also provide insights for developing novel therapeutic strategies to prevent aberrant IFN activation. The long-term goal of our lab is to understand the regulatory mechanisms of nucleic acid-elicited innate immunity. The overall objective of this proposal is to investigate the regulatory mechanisms for RIG-I-mediated innate immunity. Our pilot proteomics study found that RIG-I interacted with FIP200 (FAK-family interacting protein of 200 kDa), a well-known autophagy protein. Autophagy has a crosstalk with innate immunity and several autophagy genes suppress RIG-I signaling pathway. However, to our surprise, deficiency of FIP200 abolishes 5` triphosphate RNA and dsRNA-induced type I IFN expression and promotes RNA virus replication, such as the vesicular stomatitis virus (VSV). Interestingly, FIP200 is also known as the PP1 regulatory subunit 131 (PPP1R131), but its role in PP1 dephosphorylation is unknown. Based on the existing literature and our preliminary data, we propose the central hypothesis that FIP200 is essential for dsRNA-mediated innate immunity by regulating RIG-I dephosphorylation and oligomerization. We will investigate the following aims: Aim 1: Determine the molecular basis for the role of FIP200 in RIG-I signaling pathway. Aim 2: Determine the mechanisms by which FIP200 promotes RIG-I activation. Aim 3: Determine the in vivo interaction between FIP200 and RIG-I using a mouse model. Dysregulation of IFN responses can result in decreased resistance to viral infection or detrimental effects due to an overactive immune system. This proposal investigates the molecular mechanisms by which FIP200 controls innate immune responses to viral infection. The mechanistic concepts derived from this proposal will not only fill the knowledge gap on RIG-I regulation, but also provide insights for antiviral therapeutics.

项目总结