Macrophage-Specific E3 Ubiquitin Ligase TRIM31 Reduces Atherosclerotic Plaque Formation by Targeting LOX-1

作者：Jie Zhang, Liwen Yu, Wei� Yang, Lei Cao, Xiaohong Wang, Chunyu Kao, Zijing Li, Ruiqing Ren, Wenqian Qi, Lijuan Lyu, Wenjing Xiong, Wenhai Sui, Xiao Wu, Na Li, Bingjie Liu, Shasha Wang, Peili Bu, Yun Zhang, Chengjiang Gao, Cheng Zhang, Meng Zhang · 发表于：Circulation · 年份：2025 · DOI：10.1161/circulationaha.125.076514 · 被引用次数：5 · 研究领域：interferon and immune responses、Atherosclerosis and Cardiovascular Diseases、Immune cells in cancer

BACKGROUND: Atherosclerosis is a chronic inflammatory disease marked by lipid accumulation and immune cell infiltration in arterial walls. Macrophages contribute by internalizing oxidized low-density lipoprotein, forming foam cells, and driving inflammation. The ubiquitin–proteasome system regulates immune and inflammatory responses in atherosclerosis. This study investigated the protective role of TRIM31 (tripartite motif-containing 31), an E3 ubiquitin ligase, in macrophage lipid metabolism and inflammation through selective regulation of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1). METHODS: Transcriptomic profiling, macrophage-specific Trim31 knockout ( Trim31 fl/fl Lyz2 cre ) and overexpression ( Trim31 Lyz2-KI ) mice, and Lox-1 knockout ( Lox-1 −/− ) models were used to examine the impact of TRIM31 in vivo (n=8 per group). TRIM31 substrates were identified using single-cell RNA sequencing of atherosclerotic aortas and proteomic/immunoprecipitation–mass spectrometry analyses. Functional assays were performed in both mouse and human macrophages (n=5–6 per group). Ubiquitination mechanisms were clarified through immunoprecipitation and site-directed mutagenesis. Rescue experiments involved Lox-1 knockdown or reconstitution with wild-type and lysine 12 to arginine variant (K12R) Lox-1 and Trim31 overexpression in Lox-1 −/− or Apoe −/− Lox-1 −/− mice to evaluate the functional importance of Lox-1 ubiquitination in vivo (n=8 per group) and in vitro (n=5 per...