Xu Haixia, Yu Wenjun, Sun Shiqun, Li Congye, Ren Jun, Zhang Yingmei
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; Department of Cardiology, Affiliated Hospital of Nantong University, Nantong 226001, China.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
Sci Bull (Beijing). 2021 Aug 30;66(16):1669-1683. doi: 10.1016/j.scib.2021.01.030. Epub 2021 Jan 28.
Acute myocardial infarction (MI), one of the most common cardiovascular emergencies, is a leading cause of morbidity and mortality. Ample evidence has revealed an essential role for inflammasome activation and autophagy in the pathogenesis of acute MI. Tax1-binding protein 1 (TAX1BP1), an adaptor molecule involved in termination of proinflammatory signaling, serves as an important selective autophagy adaptor, but its role in cardiac ischemia remains elusive. This study examined the role of TAX1BP1 in myocardial ischemic stress and the underlying mechanisms involved. Levels of TAX1BP1 were significantly downregulated in heart tissues of patients with ischemic heart disease and in a left anterior descending (LAD) ligation-induced model of acute MI. Adenovirus carrying TAX1BP1 was delivered into the myocardium. The acute MI induced procedure elicited an infarct and cardiac dysfunction, the effect of which was mitigated by TAX1BP1 overexpression with little effect from viral vector alone. TAX1BP1 nullified acute MI-induced activation of the NLRP3 inflammasome and associated mitochondrial dysfunction. TAX1BP1 overexpression suppressed NLRP3 mitochondrial localization by inhibiting the interaction of NLRP3 with mitochondrial antiviral signaling protein (MAVS). Further investigation revealed that ring finger protein 34 (RNF34) was recruited to interact with TAX1BP1 thereby facilitating autophagic degradation of MAVS through K27-linked polyubiquitination of MAVS. Knockdown of RNF34 using siRNA nullified TAX1BP1 yielded protection against hypoxia-induced MAVS mitochondrial accumulation, NLRP3 inflammasome activation and associated loss of mitochondrial membrane potential. Taken together, our results favor a cardioprotective role for TAX1BP1 in acute MI through repression of inflammasome activation in a RNF34/MAVS-dependent manner.
急性心肌梗死（MI）是最常见的心血管急症之一，是发病和死亡的主要原因。大量证据表明，炎性小体激活和自噬在急性心肌梗死的发病机制中起重要作用。Tax1结合蛋白1（TAX1BP1）是一种参与促炎信号终止的衔接分子，作为一种重要的选择性自噬衔接子，但其在心脏缺血中的作用仍不清楚。本研究探讨了TAX1BP1在心肌缺血应激中的作用及其潜在机制。在缺血性心脏病患者的心脏组织以及左前降支（LAD）结扎诱导的急性心肌梗死模型中，TAX1BP1水平显著下调。携带TAX1BP1的腺病毒被导入心肌。急性心肌梗死诱导过程引发梗死和心脏功能障碍，TAX1BP1过表达减轻了这种影响，而单独的病毒载体几乎没有效果。TAX1BP1消除了急性心肌梗死诱导的NLRP3炎性小体激活和相关的线粒体功能障碍。TAX1BP1过表达通过抑制NLRP3与线粒体抗病毒信号蛋白（MAVS）的相互作用，抑制了NLRP3的线粒体定位。进一步研究发现，环指蛋白34（RNF34）被招募与TAX1BP1相互作用，从而通过MAVS的K27连接的多聚泛素化促进MAVS的自噬降解。使用siRNA敲低RNF34消除了TAX1BP1对缺氧诱导的MAVS线粒体积累、NLRP3炎性小体激活和相关线粒体膜电位丧失的保护作用。综上所述，我们的结果支持TAX1BP1在急性心肌梗死中通过以RNF34/MAVS依赖的方式抑制炎性小体激活发挥心脏保护作用。
