University of Oklahoma Health Sciences Center, Oklahoma City, OK (J.C., Y.D., C.J., R.Q., X.W., D.N.R., B.L., J.D., B.S., J.W., H.Z., C.H., K.-M.F., H.C.R., M.S.W., T.K., F.A.H., J.F.P., X.A.Z.).
Oklahoma Medical Research Foundation, Oklahoma City, OK (J.D.W., C.G., C.B.G.).
Circ Res. 2024 May 10;134(10):1330-1347. doi: 10.1161/CIRCRESAHA.123.323190. Epub 2024 Apr 1.
Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown.
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.
Endothelial ablation of 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 (interferon-induced transmembrane protein 3), 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.
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.
四跨膜蛋白 CD151 在血管内皮细胞中高度表达，并增强细胞黏附，但它在血管炎症中的作用在很大程度上仍是未知的。
对基因修饰的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，以及对 CD151 相关事件进行计算机系统生物学和生物信息学分析。
内皮细胞中敲除 导致肺部和心脏炎症、严重败血症和致命的 COVID-19，并且炎症导致内皮细胞 CD151 下调。从机制上讲，CD151 抑制内皮细胞释放促炎分子，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，并限制携带细胞因子（如 ANGPT2）和蛋白酶（如组织蛋白酶 D）的外泌体的产生。在分子水平上，CD151 将 VCP（含有泛素结合结构域的蛋白）/p97 对接在内质溶酶体上，通过介导去泛素化来促进蛋白降解，从而控制蛋白质量。在内质溶酶体膜上，CD151 将 VCP/p97 与（1）干扰素诱导跨膜蛋白 3（IFITM3）连接起来，IFITM3 调节多泡体的功能，从而抑制 IFITM3 介导的外泌体分选，（2）V-ATPase，决定内质溶酶体 pH，以支持 V-ATPase 的功能性组装。
与 CD151 在细胞表面增强细胞黏附的典型功能不同，CD151 通过维持 VCP/p97 介导的蛋白展开和周转来维持内体溶酶体的功能。通过支持蛋白质量控制和蛋白降解，CD151 防止蛋白（1）在内质溶酶体中积累，（2）通过外泌体排出，从而限制血管炎症。此外，我们的研究概念化认为内皮细胞中蛋白降解和排出之间的平衡决定了血管信息。因此，内皮细胞内质溶酶体上的 IFITM3/V-ATPase-四跨膜蛋白-VCP/p97 复合物作为一种蛋白质量控制和炎症抑制机制，可能有益于针对血管炎症的治疗干预。
