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Background <p>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.</p> Methods <p>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&#xa0;umbilical&#xa0;vein&#xa0;endothelial&#xa0;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<sup>−/−</sup> mice.</p> Results <p>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&#xa0;proteasomal&#xa0;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.</p> Conclusions <p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月30日

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  • Meng Shu,
  • Wenzhuo Cheng,
  • Fangyang Yu,
  • Liyin Zhang,
  • Li Wang,
  • Yan Shu,
  • Ruonan Wang,
  • Baorui Xue,
  • Si Jin

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Graphical Abstract