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Regulation of Proinflammatory Cytokine Responses by a Caspase-8-N4BP1 Axis

Caspase-8-N4BP1 轴对促炎细胞因子反应的调节

基本信息

批准号：
10704065
负责人：
Alexander Gitlin
金额：
$ 44.25万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-13 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704065
关键词：
Adaptor Signaling Protein Affect Agonist Anti-Inflammatory Agents Apoptosis Apoptotic Appointment Area Autoimmunity Award Binding Proteins Biochemistry Biological Process Biology CASP8 gene CD95 Antigens Career Mobility Caspase Cell Culture Techniques Cell Death Cells Cellular Immunology Cessation of life Clinical Clinical Competence Clinical Pathology Clustered Regularly Interspaced Short Palindromic Repeats Communicable Diseases Competence Data Dedications Disease Disease Progression Endowment Evaluation Faculty Funding Gene Expression Genetic Genetic Transcription Genetically Engineered Mouse Goals Health High-Throughput Nucleotide Sequencing Human Image Immune Immune System Diseases Immunity Immunologic Deficiency Syndromes Immunologic Receptors Impairment In Vitro Inflammation Inflammatory Inflammatory Response Pathway Institution Knock-in Knowledge Laboratories Leadership Licensing Ligands Link Macrophage Malignant Neoplasms Mediating Medical Medicine Mentors Mentorship Molecular Mutation NF-kappa B Natural Immunity Nerve Degeneration Pathologic Pathology Pathway interactions Patients Peer Review Phase Phosphotransferases Physicians Positioning Attribute Postdoctoral Fellow Production Proteins Publications Regulation Research Research Personnel Research Proposals Residencies Resistance Role Rotation Scientist Series Signal Pathway Signal Transduction Source Students System T-Lymphocyte TBK1 gene TLR1 gene TLR3 gene TLR4 gene TLR7 gene TNF gene TNFSF6 gene Techniques Technology Therapeutic Intervention Toll-like receptors Training Transcript Transferable Skills United States National Institutes of Health Universities Visit Work adaptive immunity autoimmune lymphoproliferative syndrome autoinflammatory diseases career constriction cytokine expectation experience faculty support genome editing genome-wide immune activation in vivo insight instructor meetings new therapeutic target novel novel therapeutic intervention phosphoproteomics response senior faculty single cell analysis undergraduate student

项目摘要

Project Summary/Abstract Rare monogenic immune disorders have illuminated key aspects of inflammation, but many of the underlying mechanisms remain poorly understood. For example, autoimmune lymphoproliferative syndrome (ALPS), a disorder in which T cells fail to undergo apoptosis, is most often caused by genetic defects in the death receptor FAS or its ligand FASL. However, mutations in caspase-8 or its adaptor FADD – which mediate cell death downstream of FAS – cause a combination of ALPS plus severe immunodeficiency. Since immunodeficiency is not generally observed in patients with FAS or FASL mutations, I hypothesized that FADD-caspase-8 must have an apoptosis-independent function downstream of an immune receptor other than FAS. Indeed, I recently discovered that activation of multiple immune receptors elicits the caspase-8-mediated cleavage of Nedd4- binding protein 1 (N4BP1), a novel cytokine suppressor. This represents a critical point of regulation during inflammation. Notably, deletion of N4BP1 does not ordinarily affect the TRIF-dependent subset of toll-like receptors (TLRs) that activate caspase-8 (e.g., TLR3 and TLR4). However, the impaired cytokine production of caspase-8-deficient macrophages stimulated with a TLR4 agonist is restored to normal by co-deletion of N4BP1. In contrast, N4BP1 deletion leads to exorbitant cytokine responses by the TRIF-independent TLRs (e.g., TLR1/2, TLR7 and TLR9) that do not directly activate caspase-8. Thus, N4BP1 cleavage by caspase-8 inactivates the anti-inflammatory activity of intact, un-cleaved N4BP1. These findings offer a novel mechanistic explanation for immunodeficiency caused by FADD-caspase-8 mutations, whereby the inability to cleave N4BP1 results in its aberrant persistence and constriction of cytokine responses. Like TLR3 and TLR4 agonists, tumor necrosis factor (TNF) also leads to caspase-8 cleavage of N4BP1, endowing TNF with the ability to inactivate N4BP1 and thereby license cytokine production by the TRIF-independent TLRs. This latter finding highlights a key point of molecular crosstalk between the TNF and TLR systems that converges on caspase-8 cleavage of N4BP1. In the current proposal, I have linked the mechanism by which N4BP1 suppresses cytokine production to a series of proteins with both previously recognized and heretofore unknown roles in inflammation. In Aim 1, I will attempt to decipher the mechanism by which N4BP1 controls the activity of this novel kinase-dependent pathway that suppresses inflammation. In Aim 2, I will dissect how N4BP1 suppresses late phase inflammatory gene expression using genome-scale technologies. In Aim 3, I will explore the mechanisms and in vivo consequences of signal integration by the TNF-caspase-8-N4BP1 axis. Together, these aims will provide novel mechanistic insights explaining a key regulatory circuit underlying inflammation. They also will serve to launch my independent research career.

项目总结/文摘