期刊
EMBO REPORTS
卷 21, 期 7, 页码 -出版社
WILEY
DOI: 10.15252/embr.201948192
关键词
autophagy; centriolar satellites; endothelial cells; GABARAP; SQSTM1; p62
资金
- British Heart Foundation (BHF) [FS/11/52/29018, FS/14/7/30574]
- Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund (ISSF3)
- MRC-IMPC Pump Priming Award [MR/R014353/1]
- Edinburgh BHF Research Excellence Award
- MRC [MR/R014353/1] Funding Source: UKRI
Autophagy is an essential cellular quality control process that has emerged as a critical one for vascular homeostasis. Here, we show that trichoplein (TCHP) links autophagy with endothelial cell (EC) function.TCHPlocalizes to centriolar satellites, where it binds and stabilizesPCM1. Loss ofTCHPleads to delocalization and proteasome-dependent degradation ofPCM1, further resulting in degradation ofPCM1's binding partnerGABARAP. Autophagic flux under basal conditions is impaired inTHCP-depletedECs, andSQSTM1/p62 (p62) accumulates. We further show thatTCHPpromotes autophagosome maturation and efficient clearance of p62 within lysosomes, without affecting their degradative capacity. ReducedTCHPand high p62 levels are detected in primaryECs from patients with coronary artery disease. This phenotype correlates with impairedECfunction and can be ameliorated byNF-kappa Binhibition. Moreover, Tchp knock-out mice accumulate of p62 in the heart and cardiac vessels correlating with reduced cardiac vascularization. Taken together, our data reveal thatTCHPregulates endothelial cell function via an autophagy-mediated mechanism.
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