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Mechanisms of a Novel Combined Immunodeficiency Caused by a Homozygous Mutation in COPG1

COPG1 纯合突变引起的新型联合免疫缺陷的机制

基本信息

批准号：
10394995
负责人：
RAIF SALIM GEHA
金额：
$ 44.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
2018-05-03 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394995
关键词：
ADP-Ribosylation Factors Age Antibody Response Apoptosis Arginine B cell differentiation B-Lymphocytes Bacteria Bacterial Infections Binding Birth CD4 Positive T Lymphocytes CDC42 gene Capsid Proteins Cell Count Cell Survival Cell physiology Cells Coat Protein Complex I Complex Coupling Cytomegalovirus Cytosol Data Defect Disease Disease model Encapsulated Endoplasmic Reticulum Ensure Family Fibroblasts GTPase-Activating Proteins Golgi Apparatus Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Human Herpesvirus 4 Immunity Immunoglobulin G Immunoglobulins Immunologic Deficiency Syndromes Impairment In Vitro Integral Membrane Protein Interleukin-4 KDEL receptor Link Lung infections Lymphocytic choriomeningitis virus Lymphopenia Lysine Mediating Membrane Molecular Chaperones Monomeric GTP-Binding Proteins Mus Mutant Strains Mice Mutation Outcome Study Patients Pharmaceutical Preparations Pneumococcal Infections Preclinical Testing Predisposition Production Proteins Recurrence Retrieval Role Secondary to Siblings Side System T-Lymphocyte Testing Transcript Treatment Efficacy Vesicle Viremia Virus Diseases chronic infection consanguineous family endoplasmic reticulum stress hypogammaglobulinemia in vivo inhibitor lysyl-aspartyl-glutamyl-leucine man mutant mutant mouse model novel preclinical efficacy protein folding protein transport receptor receptor binding recruit response retrograde transport tauroursodeoxycholic acid trafficking vesicle transport

项目摘要

We identified a biallelic K652E mutation in the γ1-COP subunit of the heptameric coat protein I (COPI) complex in 5 Omani siblings, suffering from recurrent pulmonary infections with encapsulated bacteria, CMV and EBV viremia. The four older siblings presented with severe CD4+ T cell lymphopenia and increased T cell apoptosis; the youngest had normal T cell numbers shortly after birth, but developed CMV viremia and CD4+ T cell lymphopenia at 6 mo. Coat proteins deform membranes to generate transport vesicles. They also bind to cargo proteins to properly sort them into these vesicles, and ensure their transport to specific intracellular compartments. In the early secretory system, the COPII complex transports cargo from the endoplasmic reticulum (ER) to the Golgi, while the COPI complex transports select cargo in the other direction, from the Golgi to the ER, and additionally mediates CDC42-dependent transport through the Golgi. Specific sequences on cargo proteins recognized by COPI include the di-lysine and the di-arginine motifs. Coat proteins can also bind indirectly to COPI through transmembrane proteins that act as cargo receptors. These include the KDEL receptor (KDELR), which links COPI (residing on the cytosolic side of Golgi membrane) to soluble proteins within the Golgi (lumenal side) that have a KDEL sequence. KDEL proteins are abundant ER proteins involved in protein folding (chaperones). A fraction of KDEL proteins leak from the ER, and are retrieved from the Golgi to the ER through the KDELR and COPI. Defect in this retrieval leads to the loss of ER chaperones, which has been found to induce ER stress. Preliminary data show that fibroblasts from patients, and mice homozygous for the K652E γ1-COP mutation, express the mutant protein, but demonstrate defective COPI-mediated trafficking, and that the mutation disrupts the binding of the mutant COPI complex to KDELR. Mutant mice have severe hypogammaglobulinemia and poor antibody responses. Their B cells had increased ER stress and impaired immunoglobulin (Ig) secretion that was rescued by the ER stress inhibitor TUDCA. T cells from the mutant were normal in numbers, but had increased ER stress, and displayed increased apoptosis and diminished IL-4 production following sustained activation in vitro. We propose to test the hypothesis that the γ1-COP mutation disrupts COPI-mediated trafficking causing increased ER stress that impairs B and T cell function, increases susceptibility to bacterial and viral infection, and results in CD4+ T cell lymphopenia secondary to persistent viral infection. The studies proposed will elucidate the mechanisms by which a novel monogenic defect that impairs COPI-mediated trafficking leads to CID with CD4+ T cell lymphopenia, and will test pre-clinically the therapeutic efficacy of ER stress relieving drugs in this disease.

我们在七聚体外壳蛋白I （COPI）的γ - 1- cop亚基中发现了一个双等位基因K652E突变。