TMEM230促进抗原加工,贩运,并通过调节膜结合细胞器的内膜系统(溶酶体,蛋白体和线粒体)和吞噬体。免疫系统的激活需要在内膜系统和细胞质膜之间运输各种货物。高尔基体是内膜系统的枢纽,对生成至关重要,维护,回收,以及内膜系统本身和免疫系统的成分的贩运。免疫系统成分的细胞内运输和分泌取决于用于ATP合成的线粒体金属蛋白,该ATP为内膜货物的运动蛋白运输提供动力。聚糖修饰酶基因和运动蛋白对于激活免疫系统和内膜系统与质膜之间的抗原运输至关重要。最近,TMEM230被鉴定为与溶酶体中的RNASET2以及各种细胞类型和细胞器中的金属蛋白共同调节,包括自身免疫性疾病中的线粒体。在类风湿关节炎(RA)中,运动蛋白分泌异常的金属蛋白酶是滑膜组织重塑和关节组织破坏的主要原因,骨侵蚀,和软骨的吞噬细胞的损失。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中起作用的某些细胞类型(成纤维细胞或内皮细胞)中,特定的聚糖加工酶被上调.TMEM230被确定为OA和RA中金属蛋白酶和乙酰肝素酶必需的组织重塑分泌的调节剂。在树突状(DC)中,自然杀伤和T细胞,与OA相比,TMEM230在RA中以低水平表达或不表达。DC中的TMEM230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并防止对自身免疫性疾病的易感性所必需的。为了确定TMEM230和内膜系统如何有助于我们研究的自身免疫,聚糖修饰酶,通过分析来自RA患者来源的滑膜组织的已发表的单细胞转录组数据集来分析滑膜组织中与TMEM230共同调节或由TMEM230调节的金属蛋白酶和运动蛋白基因。
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.