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Negative regulation of innate immune signaling pathways by the selective autophagy receptor TAX1BP1

选择性自噬受体 TAX1BP1 对先天免疫信号通路的负调节

基本信息

批准号：
10276931
负责人：
EDWARD W HARHAJ
金额：
$ 64.29万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10276931
关键词：
Acute Adaptor Signaling Protein Agonist Amyotrophic Lateral Sclerosis Apoptosis Apoptotic Automobile Driving Autophagocytosis Autophagosome Biological CASP1 gene CRISPR/Cas technology Cell Death Cell membrane Cells DNA DNA Viruses Data Dinucleoside Phosphates Double-Stranded RNA Endoplasmic Reticulum Gene Expression Genes Goals Golgi Apparatus Herpesvirus 1 Homeostasis Host Defense Huntington Disease IRF3 gene Immune Immune response Immune signaling Inflammasome Inflammation Inflammatory Inflammatory Response Interferon Type I Interferon-alpha Interferon-beta Interferons Invaded Investigation Knock-out Knockout Mice Lytic Mass Spectrum Analysis Mediating Mitochondria Modeling Molecular Mus NF-kappa B Natural Immunity Pathogenicity Pathway interactions Pattern Pattern recognition receptor Periodicity Peritoneal Phosphorylation Phosphorylation Site Phosphotransferases Play Principal Investigator Production Proteins RNA Helicase RNA Viruses Reagent Receptor Signaling Regulation Reporting Research Personnel Role Signal Pathway Signal Transduction Signaling Protein Specificity Stimulator of Interferon Genes TBK1 gene Testing Tissues Transcriptional Activation Viral Genome Virus Work Zinc Fingers activating transcription factor adaptive immune response adaptive immunity base cell type cytokine ds-DNA genomic RNA immunoregulation in vivo inhibitor/antagonist innate immune pathways insight macrophage mutant novel pathogen pathogenic microbe prevent protein TDP-43 protein aggregation receptor reconstitution recruit response sensor tool transcription factor viral genomics virology

项目摘要

ABSTRACT Innate immunity provides the first line of host defense in response to invading pathogens. Pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs) in viruses and other pathogens. RIG-I/MDA-5 are DExD/H box RNA helicases in the RIG-I-like receptor (RLR) pathway that detect double stranded RNA viral genomes and activate the mitochondrial adaptor protein MAVS. The DNA sensor cGAS detects double stranded DNA and activates STING, a transmembrane endoplasmic reticulum adaptor. Both MAVS and STING activate canonical (IKKa and IKKb), and noncanonical IKK kinases (TBK1 and IKKi) to activate transcription factors NF-kB and IRF3 respectively. Together, IRF3 and NF-kB regulate the expression of type I interferon (IFN) and inflammatory genes that coordinate the innate response and initiate the adaptive immune response against pathogens. The NLRP3 inflammasome also plays a critical role in inflammatory responses by triggering caspase-1-mediated pro-IL-1b cleavage to yield the biologically active form of IL- 1b that drives inflammation and adaptive immunity. NLRP3 also induces a highly lytic form of inflammatory cell death termed pyroptosis via cleavage of gasdermin-D to form plasma membrane pores. The RLR, cGAS- STING and NLRP3 inflammasome pathways are potent inducers of inflammation that must be tightly regulated to avert overexuberant inflammation and tissue damage. TAX1BP1 was first identified as an anti-apoptotic protein that interacts with the zinc finger deubiquitinase A20/TNFAIP3. Our previous work has established that TAX1BP1 restricts cytokine-induced NF-kB activation as well as RLR-induced type I IFN production and apoptosis. TAX1BP1 functions as a selective autophagy receptor by recruiting ubiquitinated cargo to developing autophagosomes via two LC3 interaction regions (LIRs). However, it remains unclear how TAX1BP1 autophagy function is regulated and if TAX1BP1 inhibits other innate immune signaling pathways. In preliminary studies we provide experimental evidence that TAX1BP1 is phosphorylated by both noncanonical and canonical IKK kinases which controls both basal and virus-induced TAX1BP1 autophagic degradation respectively. Using TAX1BP1-deficient macrophages we have demonstrated that TAX1BP1 is a novel inhibitor of both cGAS-STING and NLRP3 pathways. Furthermore, MAVS protein aggregates accumulate in TAX1BP1- deficient cells suggesting a potential aggrephagy function in the regulation of innate immune signaling. The central hypothesis driving the proposed investigations is that TAX1BP1 inhibits RLR, cGAS-STING and NLRP3 pathways by autophagy-mediated clearance of signaling protein aggregates. We will test this hypothesis experimentally with the following Specific Aims: (1) determine the role of TAX1BP1 phosphorylation in its autophagy function, (2) determine the mechanisms of TAX1BP1 inhibition of the cGAS-STING pathway, and (3) determine the mechanisms of TAX1BP1 inhibition of the NLRP3 pathway. Completion of the proposed studies will provide new insights into innate immune regulation and immune homeostasis.

摘要