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Regulation of TLR signaling, Inflammation and Antigen Presentation by VPS33B

VPS33B 对 TLR 信号传导、炎症和抗原呈递的调节

基本信息

批准号：
10439913
负责人：
Helmut J Kramer
金额：
$ 67.9万
依托单位：
CINCINNATI CHILDRENS HOSP 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：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10439913
关键词：
Affect Antigen Presentation Antigen Presentation Pathway Apoptotic Arthrogryposis Bacteremia Bacteria Bacterial Infections Binding C Type Lectin Receptors CD8-Positive T-Lymphocytes Cell membrane Cell surface Cells Cessation of life Cholestasis Complex Data Dendritic Cells Development Disease Drosophila genus Early Endosome Endocytosis Endosomes Event Exposure to Failure Family Genes Goals Human Immune response Immune signaling Immunity Inflammation Inflammatory Inflammatory Response Innate Immune Response Innate Immune System Investigation Ligands Link MHC Class II Genes Membrane Fusion Microbe Molecular Mus Mutate Mutation Natural Immunity Necrosis Outcome Pathway interactions Patients Pattern recognition receptor Phagocytes Phagocytosis Phagosomes Phosphotransferases Play Proteins Publishing Receptor Activation Receptor Signaling Recurrence Regulation Role Sampling Sepsis Signal Transduction Signal Transduction Pathway Specificity Symptoms Syndrome T cell response TLR4 gene Testing Toll-like receptors Translating Vertebrates adaptive immunity antimicrobial base cell type cytokine fly human disease in vivo insight kidney dysfunction macrophage microbial mutant novel therapeutics paralogous gene protein function receptor recruit response trafficking unpublished works

项目摘要

Project Summary Initiation of innate immune responses depends on cognate interaction between germline-encoded pattern recognition receptors and their ligands (expressed by microbes). Following recognition, the receptors initiate activation of downstream signal transduction pathways that often involve recruitment of downstream adapters and kinases. The Toll-like receptor family of PRRs, which are the subject of current investigation, are expressed both on the plasma membrane and in the endosomes. Several recent studies have demonstrated that endocytosis of the plasma membrane TLRs (especially TLR4) plays a critical role in regulating both quality and magnitude of inflammatory responses in a responding macrophage. Other studies have demonstrated that TLR signaling enhances phagocytosis of microbial cargo but not of apoptotic cell cargo suggesting a degree of specificity that is not understood. In addition, although endocytosis of TLR4 and the events following endocytosis of TLR4 that influence signal transduction are very well studied, it is not entirely clear if and how endocytosis influences signaling downstream of other plasma membrane and endosomal TLRs. In our studies, we find that a protein called Vps33B regulates handling of the phagocytic and endocytic cargo following pattern recognition receptor activation. More importantly, Vps33B directly influences the outcome of signaling downstream of TLRs in mice and Toll- and IMD pathways in Drosophila. Mutations in the genes VPS33B and VPS16B are linked to a rare human disease called ARC (Arthrogryposis-renal dysfunction-cholestasis) syndrome. Both of these ARC genes encode paralogs of HOPS complex subunits suggesting a role in membrane fusions but how perturbation of function of these proteins results in a diverse spectrum of disease symptoms in ARC patients is not entirely clear. It has however been documented that ARC patients suffer from sepsis and recurrent bacterial infections and we were therefore investigated the role of these proteins in influencing immune responses. We find that in the absence of VPS33B, Drosophila respond vigorously to microbial insult. Exaggerated immune responses are generated in response to live or dead bacteria and purified ligands of the Toll and IMD pathway results in death of Vps33B mutant, but not wild-type flies. This function of Vps33B is conserved in vertebrates and we find that mouse macrophages lacking Vps33B secrete very high quantities of inflammatory cytokines, when stimulated by either plasma membrane or endosomal TLR ligands. We therefore hypothesize that activation of pattern recognition receptors and specifically TLRs leads to formation of specialized endosomes that depend on Vps33B for lysosomal fusion. Lack of Vps33B is likely to affect several aspects of innate and adaptive immunity and to test this hypothesis, we propose to 1. Define the molecular events that regulate Vps33B function in endosomal maturation, 2. Define the role of Vps33B-regulated TLR trafficking and signaling 3. Investigate the role of Vps33B in regulating cargo handling by DCs and 4. Investigate the role of Vps33B in regulating antigen presentation and adaptive immunity.

项目总结