Liu Qiang, Yan Lu, Wu Tao, Wu Qinghua, Ke Ben, Shen Wen
Department of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Department of Cardiovascular Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China.
Commun Biol. 2025 Mar 19;8(1):457. doi: 10.1038/s42003-025-07839-w.
The activation of pyrin domain-containing-3 (NLRP3) inflammasome in macrophages is a risk factor accelerating the progression of atherosclerosis (AS). Here, the function of pellino 1 (Peli1) in regulating the activation of NLRP3 inflammasome during the development of AS was investigated. Our results showed that Y-box binding protein 1 (YB-1) knockdown could inhibit the progression of AS in vivo, and YB-1 silencing repressed oxidized low-density lipoprotein (ox-LDL)-mediated lipid accumulation and inflammation in macrophages by inactivating NLRP3 inflammasome. E3 ubiquitination ligase Peli1 mediated ubiquitination-dependent degradation of YB-1 during AS progression. Moreover, it was found that YTH domain-containing 2 (YTHDC2) recognized methyltransferase-like 3 (METTL3)-mediated Peli1 N6-methyladenosine (mA) modification and mediated Peli1 mRNA degradation. Rescue studies revealed that YB-1 upregulation abrogated the repressive effect of Peli1 upregulation on AS progression both in vitro and in vivo. Taken together, Peli1, regulated by mA modification, inhibited YB-1-mediated activation of NLRP3 inflammasome in macrophages by promoting YB-1 ubiquitination to suppress the progression of AS.
巨噬细胞中含吡啉结构域蛋白3（NLRP3）炎性小体的激活是加速动脉粥样硬化（AS）进展的一个危险因素。在此，研究了pellino 1（Peli1）在AS发生发展过程中调节NLRP3炎性小体激活的功能。我们的结果表明，敲低Y盒结合蛋白1（YB-1）可在体内抑制AS进展，且沉默YB-1可通过使NLRP3炎性小体失活来抑制巨噬细胞中氧化型低密度脂蛋白（ox-LDL）介导的脂质蓄积和炎症。E3泛素连接酶Peli1在AS进展过程中介导YB-1的泛素化依赖性降解。此外，发现含YTH结构域蛋白2（YTHDC2）识别甲基转移酶样3（METTL3）介导的Peli1 N6-甲基腺苷（m6A）修饰并介导Peli1 mRNA降解。挽救实验表明，上调YB-1可消除上调Peli1对体外和体内AS进展的抑制作用。综上所述，受m6A修饰调控的Peli1通过促进YB-1泛素化来抑制巨噬细胞中YB-1介导的NLRP3炎性小体激活，从而抑制AS进展。
