CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.
CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.
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CD151 维持内溶酶体蛋白质量以抑制血管炎症。
DOI：
10.1161/circresaha.123.323190
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发表时间：
2024
影响因子：
20.1
通讯作者：
Subramaniyan,Bhara
中科院分区：
文献类型：
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作者：
Chen,Junxiong;Ding,Yingjun;Jiang,Chao;Qu,Rongmei;Wren,JonathanD;Georgescu,Constantin;Wang,Xuejun;Reuter,DarleneN;Liu,Beibei;Giles,CoryB;Mayr,ChristophH;Schiller,HerbertB;Dai,Jingxing;Stipp,ChristopherS;Subramaniyan,Bhara
背景：TetraspanCD151在血管内皮细胞中高表达，能促进细胞黏附，但其在血管炎症中的作用尚不清楚。方法体外转基因内皮细胞的分子和细胞生物学分析，基因工程小鼠模型的体内血管生物学分析，以及CD151相关事件的硅系统生物学和生物信息学分析。结果内皮消融CD151导致肺和心脏炎症，严重的败血症和危险的新冠肺炎，内皮CD151在炎症中表达下调。从机制上讲，CD151抑制内皮细胞释放促炎分子，从而减少白细胞的渗透。在亚细胞水平上，CD151决定了多囊泡体/溶酶体的完整性，并限制了携带细胞因子如血管生成素-2(Angiopoietin-2)和蛋白酶如组织蛋白酶-D的外切体的产生。在分子水平上，CD151将VCP(Valosin-Holding Protein)/p97对接到内溶酶体上，促进VCP/p97的功能。VCP/p97通过介导蛋白质降解过程中的去泛素化来控制蛋白质质量。在内溶酶体膜上，CD151将VCP/p97与(1)IFITM3(干扰素诱导的跨膜蛋白3)连接，以抑制IFITM3介导的外体分选；(2)V-ATPase，决定内溶酶体的pH，以支持V-ATPas的功能组装。结论CD151从加强细胞表面黏附的典型功能出发，通过维持VCP/p97介导的蛋白质的展开和周转来维持内溶酶体的功能。通过支持蛋白质质量控制和蛋白质降解，CD151防止蛋白质(1)在内溶体中积聚，(2)通过外体排出，以限制血管炎症。此外，我们的研究概念化了内皮细胞中蛋白质的降解和释放之间的平衡决定了血管信息。因此，IFITM3/V-ATPase-Tetraspanin-VCP/p97复合体作为一种蛋白质质量控制和炎症抑制机制，可能有利于血管炎症的治疗干预。
BACKGROUNDTetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown.METHODSIn 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.RESULTSEndothelial ablation ofCd151leads 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.CONCLUSIONSDistinct 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.