通过单细胞转录组分析确定自身免疫中金属蛋白和运动蛋白的内膜调控。

3区 生物学 Q1 Biochemistry, Genetics and Molecular Biology
Edoardo Abeni, Cinzia Cocola, Stefania Croci, Valentina Martino, Eleonora Piscitelli, Roberta Gualtierotti, Paride Pelucchi, Valeria Tria, Giovanni Porta, Fabian Troschel, Burkhard Greve, Giovanni Nano, Alexey Tomilin, James Kehler, Daniela Gerovska, Daniela Mazzaccaro, Martin Götte, Marcos J Arauzo-Bravo, Salvarani Carlo, Ileana Zucchi, Rolland Reinbold
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引用次数: 0

摘要

TMEM230 通过调节膜结合细胞器(溶酶体、蛋白体和线粒体)和吞噬体的内膜系统,促进抗原的加工、运输和递呈。激活免疫系统需要在内膜系统和细胞质膜之间转运各种载体。高尔基体是内膜系统的枢纽,对内膜系统本身和免疫系统各组成部分的生成、维持、循环和贩运至关重要。免疫系统成分的胞内转运和分泌依赖于线粒体金属蛋白的 ATP 合成,而 ATP 合成又为内膜货物的运动蛋白转运提供动力。糖修饰酶基因和马达蛋白对于激活免疫系统以及在内膜系统和质膜之间转运抗原至关重要。最近发现,TMEM230 与溶酶体中的 RNASET2 以及各种细胞类型和细胞器(包括自身免疫疾病中的线粒体)中的金属蛋白酶共同调控。在类风湿性关节炎(RA)中,运动蛋白分泌金属蛋白酶的异常是导致滑膜组织重塑和关节组织破坏的主要原因,它能促进血管浸润、骨侵蚀以及吞噬细胞造成的软骨损失。在这项研究中,我们发现与骨关节炎(OA)相比,在类风湿性关节炎的破坏性组织重塑过程中,某些细胞类型(成纤维细胞或内皮细胞)中的特定糖加工酶上调。在 OA 和 RA 中,TMEM230 被确定为金属蛋白酶和肝素酶分泌的调节器,这些酶是组织重塑所必需的。在树突状细胞(DC)、自然杀伤细胞和T细胞中,与OA相比,TMEM230在RA中的表达水平较低或没有表达。TMEM230在树突状细胞中的表达可能是调节性或辅助性T细胞维持对自身抗原的耐受性和防止易患自身免疫性疾病所必需的。为了确定TMEM230和内膜系统如何促进自身免疫,我们通过分析已发表的来自RA患者滑膜组织的单细胞转录组数据集,研究了滑膜组织中与TMEM230共调或受TMEM230调控的糖修饰酶、金属蛋白酶和运动蛋白基因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Single-cell transcriptomic analysis to identify endomembrane regulation of metalloproteins and motor proteins in autoimmunity.

TMEM230 promotes antigen processing, trafficking, and presentation by regulating the endomembrane system of membrane bound organelles (lysosomes, proteosomes and mitochondria) and phagosomes. Activation of the immune system requires trafficking of various cargos between the endomembrane system and cell plasma membrane. The Golgi apparatus is the hub of the endomembrane system and essential for the generation, maintenance, recycling, and trafficking of the components of the endomembrane system itself and immune system. Intracellular trafficking and secretion of immune system components depend on mitochondrial metalloproteins for ATP synthesis that powers motor protein transport of endomembrane cargo. Glycan modifying enzyme genes and motor proteins are essential for the activation of the immune system and trafficking of antigens between the endomembrane system and the plasma membrane. Recently, TMEM230 was identified as co-regulated with RNASET2 in lysosomes and with metalloproteins in various cell types and organelles, including mitochondria in autoimmune diseases. Aberrant metalloproteinase secretion by motor proteins is a major contributor to tissue remodeling of synovial membrane and joint tissue destruction in rheumatoid arthritis (RA) by promoting infiltration of blood vessels, bone erosion, and loss of cartilage by phagocytes. In this study, we identified that specific glycan processing enzymes are upregulated in certain cell types (fibroblast or endothelial cells) that function in destructive tissue remodeling in rheumatoid arthritis compared to osteoarthritis (OA). TMEM230 was identified as a regulator in the secretion of metaloproteinases and heparanase necessary tissue remodeling in OA and RA. In dendritic (DC), natural killer and T cells, TMEM230 was expressed at low or no levels in RA compared to OA. TMEM230 expression in DC likely is necessary for regulatory or helper T cells to maintain tolerance to self-antigens and prevent susceptibility to autoimmune disease. To identify how TMEM230 and the endomembrane system contribute to autoimmunity we investigated, glycan modifying enzymes, metalloproteinases and motor protein genes co-regulated with or regulated by TMEM230 in synovial tissue by analyzing published single cell transcriptomic datasets from RA patient derived synovial tissue.

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来源期刊
Advances in protein chemistry and structural biology
Advances in protein chemistry and structural biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
7.40
自引率
0.00%
发文量
66
审稿时长
>12 weeks
期刊介绍: Published continuously since 1944, The Advances in Protein Chemistry and Structural Biology series has been the essential resource for protein chemists. Each volume brings forth new information about protocols and analysis of proteins. Each thematically organized volume is guest edited by leading experts in a broad range of protein-related topics.
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