KAP1 SUMOylates and stabilizes SR-A to facilitate glycated LDL transcytosis and accelerate atherosclerosis

Atherosclerosis (AS)-associated cardiovascular disease is the main cause of global mortality. The excessive retention of glycated low-density lipoprotein (G-LDL) under the vascular endothelium promotes AS. In addition, G-LDL supports a role in promoting the expression of scavenger receptor A (SR-A), increasing SR-A-mediated transcytosis of G-LDL in endothelial cells (ECs), consequently accelerating the progression of atherosclerosis. However, the underlying mechanism used by G-LDL to promote SR-A expression has not been elucidated, thus representing the aim of this work. The protein–protein interaction of the E3 SUMO ligase KRAB structural domain-associated protein 1 (KAP1) and SR-A were confirmed by co-immunoprecipitation (co-IP)-based immunoblotting and immunofluorescence in human umbilical vein endothelial cells (HUVECs). G-LDL uptake and transcytosis in KAP1-silencing or overexpressing HUVECs were assessed. The effect of KAP1 on de-ubiquitination and SUMOylation of SR-A was determined by co-IP-based immunoblotting. The role of KAP1 on G-LDL-induced atherosclerosis was tested by adenovirus-mediated knockdown in ApoE−/− mice. KAP1 was identified as an enhancer of SR-A, promoting its expression. KAP1 bound to SR-A and promoted SUMO1 modification of the SR-A lysine (K)22, which hampers K48-linked ubiquitination and proteasomal degradation of SR-A. KAP1 deficiency attenuated G-LDL-induced SR-A activation both in vitro and in vivo, reduced aortic G-LDL retention, and consequently, atherosclerotic vulnerable plaque formation in murine models. This study identifies a SUMOylation–ubiquitination crosstalk that governs SR-A stability, revealing KAP1 as a key molecular switch controlling SR-A turnover in endothelial cells. These findings provide a mechanistic basis for how G-LDL accelerates atherosclerosis.