Martello, A; Lauriola, A; Mellis, D; Parish, E; Dawson, JC; Imrie, L; Vidmar, M; ... Caporali, A; + view all Martello, A; Lauriola, A; Mellis, D; Parish, E; Dawson, JC; Imrie, L; Vidmar, M; Gammoh, N; Mitic, T; Brittan, M; Mills, NL; Carragher, NO; D'Arca, D; Caporali, A; - view fewer (2020) Trichoplein binds PCM 1 and controls endothelial cell function by regulating autophagy. EMBO Reports , 21 (7) , Article e48192. 10.15252/embr.201948192.

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Abstract

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. TCHP localizes to centriolar satellites, where it binds and stabilizes PCM 1. Loss of TCHP leads to delocalization and proteasome‐dependent degradation of PCM 1, further resulting in degradation of PCM 1's binding partner GABARAP . Autophagic flux under basal conditions is impaired in THCP ‐depleted EC s, and SQSTM 1/p62 (p62) accumulates. We further show that TCHP promotes autophagosome maturation and efficient clearance of p62 within lysosomes, without affecting their degradative capacity. Reduced TCHP and high p62 levels are detected in primary EC s from patients with coronary artery disease. This phenotype correlates with impaired EC function and can be ameliorated by NF ‐κB inhibition. Moreover, Tchp knock‐out mice accumulate of p62 in the heart and cardiac vessels correlating with reduced cardiac vascularization. Taken together, our data reveal that TCHP regulates endothelial cell function via an autophagy‐mediated mechanism.

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