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Chen, J.* ; Ding, Y.* ; Jiang, C.* ; Qu, R.* ; Wren, J.D.* ; Georgescu, C.* ; Wang, X.* ; Reuter, D.N.* ; Liu, B.* ; Giles, C.B.* ; Mayr, C. ; Schiller, H. B. ; Dai, J.* ; Stipp, C.S.* ; Subramaniyan, B.* ; Wang, J.* ; Zuo, H.* ; Huang, C.* ; Fung, K.M.* ; Rice, H.C.* ; Sonnenberg, A.* ; Wu, D.* ; Walters, M.S.* ; Zhao, Y.Y.* ; Kanie, T.* ; Hays, F.A.* ; Papin, J.F.* ; Wang, D.W.* ; Zhang, X.A.*

CD151 maintains endolysosomal protein quality to inhibit vascular inflammation.

Circ. Res. 134, 1330-1347 (2024)
DOI PMC
Free by publisher: Publ. Version/Full Text online available 05/2025
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cell Adhesion ; Endothelial Cells ; Multivesicular Bodies ; Proteolysis ; Ubiquitin
ISSN (print) / ISBN 0009-7330
e-ISSN 1524-4571
Journal Circulation Research
Quellenangaben Volume: 134, Issue: 10, Pages: 1330-1347 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Lung Health and Immunity (LHI)