Journal article
CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation
Circulation research, Vol.134(10), pp.1330-1347
05/10/2024
DOI: 10.1161/CIRCRESAHA.123.323190
PMCID: PMC11081830
PMID: 38557119
Abstract
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, 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.
Details
- Title: Subtitle
- CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation
- Creators
- Junxiong Chen - University of Oklahoma Health Sciences CenterYingjun Ding - University of Oklahoma Health Sciences CenterChao Jiang - University of Oklahoma Health Sciences CenterRongmei Qu - University of Oklahoma Health Sciences CenterJonathan D Wren - Oklahoma Medical Research FoundationConstantin Georgescu - Oklahoma Medical Research FoundationXuejun Wang - University of Oklahoma Health Sciences CenterDarlene N Reuter - University of Oklahoma Health Sciences CenterBeibei Liu - University of Oklahoma Health Sciences CenterCory B Giles - Oklahoma Medical Research FoundationChristoph H Mayr - Helmholtz Zentrum MünchenHerbert B Schiller - Helmholtz Zentrum MünchenJingxing Dai - University of Oklahoma Health Sciences CenterChristopher S Stipp - University of IowaBharathiraja Subramaniyan - University of Oklahoma Health Sciences CenterJie Wang - University of Oklahoma Health Sciences CenterHoujuan Zuo - University of Oklahoma Health Sciences CenterChao Huang - University of Oklahoma Health Sciences CenterKar-Ming Fung - University of Oklahoma Health Sciences CenterHeather C Rice - University of Oklahoma Health Sciences CenterArnoud Sonnenberg - The Netherlands Cancer InstituteDavid Wu - University of ChicagoMatthew S Walters - University of Oklahoma Health Sciences CenterYou-Yang Zhao - Lurie Children's HospitalTomoharu Kanie - University of Oklahoma Health Sciences CenterFranklin A Hays - University of Oklahoma Health Sciences CenterJames F Papin - University of Oklahoma Health Sciences CenterDao Wen Wang - Huazhong University of Science and TechnologyXin A Zhang - University of Oklahoma Health Sciences Center
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.134(10), pp.1330-1347
- DOI
- 10.1161/CIRCRESAHA.123.323190
- PMID
- 38557119
- PMCID
- PMC11081830
- NLM abbreviation
- Circ Res
- eISSN
- 1524-4571
- Language
- English
- Electronic publication date
- 04/01/2024
- Date published
- 05/10/2024
- Academic Unit
- Molecular Physiology and Biophysics; Biology
- Record Identifier
- 9984580297202771
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