Decreased phosphorylation facilitates the degradation of the endogenous protective molecule c-Ski in vascular smooth muscle cells

Abstract

The dysfunction of vascular smooth muscle cells (VSMCs) is critical for atherosclerosis (AS) progression. Autophagy is indispensable during phenotypic switching and proliferation of VSMCs, contribute to AS development. Cellular Sloan-Kettering Institute (c-Ski), the repressor of TGF-β signaling, is involved in diverse physiological and pathological processes. We previously defined c-Ski also as an endogenous protective molecule against AS via inhibiting abnormal proliferation and autophagy of VSMCs. However, the endogenous level of c-Ski in VSMCs is markedly decreased during the progression of AS, so that the protective effect is drastically weakened. Elucidating the molecular mechanisms is key to the understanding of AS development and treatment. We determined that oxidized low-density lipoprotein (ox-LDL) and platelet-derived growth factor (PDGF) directly induced the degradation of c-Ski protein, closely associated with reducing its phosphorylation. Serine₃₈₃ (S383) was identified as the crucial phosphorylation site for stabilizing protein expression and nuclear location of c-Ski, which was responsible for its transcriptional suppression of autophagy-related genes. Decreased S383 phosphorylation facilitated nuclear export and degradation of c-Ski, thereby lessened its inhibitory effect on induction of autophagy genes. These findings provide a novel view of c-Ski modification and function modulation under some vascular injury factors, which point to a new potential therapeutic strategy by targeting c-Ski.

Keywords: Autophagy; Cellular Sloan-Kettering Institute (c-Ski); Degradation; Serine(383) (S383) phosphorylation; Vascular smooth muscle cells (VSMCs).