BACKGROUND:Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown.METHODS:In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events.RESULTS:Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3, which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase.CONCLUSIONS:Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

中文翻译：

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CD151 维持内溶酶体蛋白质量以抑制血管炎症


背景：四跨膜蛋白CD151在内皮细胞中高表达，增强细胞粘附，但其在血管炎症中的作用仍知之甚少。方法：对转基因内皮细胞进行体外分子和细胞生物学分析，对基因工程小鼠模型进行体内血管生物学分析，并对 CD151 相关事件进行计算机系统生物学和生物信息学分析。结果： Cd151的内皮消融会导致肺部和心脏炎症、严重败血症和危险的 COVID-19，并且内皮 CD151 在炎症中下调。从机制上讲，CD151 抑制内皮释放促炎分子，从而减少白细胞浸润。在亚细胞水平上，CD151 决定多泡体/溶酶体的完整性，并限制携带 ANGPT2（血管生成素-2）等细胞因子和组织蛋白酶-D 等蛋白酶的外泌体的产生。在分子水平上，CD151 将 VCP（含缬氨肽蛋白）/p97 与内溶酶体对接，以促进 VCP/p97 功能，VCP/p97 通过介导去泛素化进行蛋白水解降解来控制蛋白质质量。在内溶酶体膜上，CD151 将 VCP/p97 连接到 (1) IFITM3（调节多囊泡体功能，以抑制 IFITM3 介导的外泌体分选）和 (2) V-ATP 酶（决定内溶酶体 pH 值）以支持 V- 的功能组装结论：与增强细胞表面细胞粘附的典型功能不同，CD151 通过维持 VCP/p97 介导的蛋白质解折叠和周转来维持内溶酶体功能。通过支持蛋白质质量控​​制和蛋白质降解，CD151 可防止蛋白质 (1) 在内溶酶体中积聚，以及 (2) 通过外泌体排出，从而限制血管炎症。 此外，我们的研究概念化了内皮细胞中蛋白质降解和释放之间的平衡决定了血管信息。因此，内溶酶体上的 IFITM3/V-ATPase-tetraspanin-VCP/p97 复合物作为蛋白质质量控​​制和炎症抑制机制，可能有益于血管炎症的治疗干预。