Trichoplein binds PCM 1 and controls endothelial cell function by regulating autophagy

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 PCM1. Loss of TCHP leads to delocalization and proteasome-dependent degradation of PCM1, further resulting in degradation of PCM1's binding partner GABARAP. Autophagic flux under basal conditions is impaired in THCP-depleted ECs, and SQSTM1/ 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 ECs from patients with coronary artery disease. This phenotype correlates with impaired EC function and can be ameliorated by NF-jB 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.

Autophagy at the interface of endothelial cell homeostasis and vascular disease

“…During autophagosome formation, PCM1 promotes the formation of GABARAP-positive autophagosome, controlling the delivery of GABARAP to the autophagosome [25]. Consistently with this study, in ECs, the keratin-binding protein trichoplein (TCHP) directly binds PCM1 in the pericentrosomal region and regulates its stability [27]. Loss of TCHP accelerates the proteasomal degradation of PCM1 and consequently of its binding partner GABARAP, thereby impairing autophagic flux.…”

“…Therefore, the accumulation of p62 could lead to hyperactivation of these pathways, promoting cellular senescence. The accumulation of p62 and protein aggregates and a premature senescent phenotype has been associated with defective autophagy in ECs lacking TCHP [27]. The phenotype is due to NF-kB activation, and it has been observed in ECs isolated from patients with coronary artery disease and endothelial dysfunction [27].…”

The Role of Decorin Proteoglycan in Mitophagy

“…This novel signaling pathway of decorin/MET/mitostatin/Parkin transduces signals from high affinity decorin/MET interactions via an unidentified kinase or similar effector, for sustained tumor cell mitophagy [174,175]. In line with our studies, it has been recently shown that mitostatin/Trichoplein binds pericentriolar material 1 protein (PCM1) and controls autophagy in endothelial cells [176]. Autophagy and mitophagy are emerging as the primary mechanisms of action that fully integrate and translate decorin/RTK antagonism across diverse tissues within the tumor into the established and classical anti-tumorigenic properties attributed to this proteoglycan.…”

Melanin Distribution in Human Skin: Influence of Cytoskeletal, Polarity, and Centrosome-Related Machinery of Stratum basale Keratinocytes

“…We show, for the first time, the apical subcellular localisation of centriolar satellites in human skin ex vivo ( Figure 3 ) and in vivo ( Figure 4 ). Centriolar satellites tend to spread throughout the cytoplasm by following the centrosome [ 58 ], and have been assessed in different cell types in culture (e.g., endothelial cells [ 59 ] or epithelial (retina) cells [ 45 , 60 ]). The intracellular localisation of centriolar satellites can be disrupted by either increasing their dispersion throughout the cytoplasm, or by causing them to accumulate around the centrosome [ 61 ].…”