Coxsackievirus B3 Employs Viperin Protein Revived by the 3C Protease to Induce Acute Heart Failure via SGK1-KCNQ1 Signaling

Coxsackievirus B3 (CVB3)-induced acute heart failure (AHF) is a common cause of cardiogenic death in young and middle-aged people. However, the key molecular events linking CVB3 to AHF remain largely unknown, resulting in a lack of targeted therapy strategies so far. Here, we unexpectedly found that deficiency of Viperin does not promote CVB3 infection but protects mice from CVB3-induced AHF. Importantly, cardiac-specific expression of Viperin can induce cardiac dysfunction. Mechanistically, CVB3-3C protease rescues Viperin protein expression in cardiomyocytes by cleaving UBE4A. Viperin in turn recruits and reduces STAT1 to activate SGK1-KCNQ1 signaling, which leads to cardiac electrical dysfunction and subsequent AHF. Furthermore, we designed an interfering peptide VS-IP1, which blocked Viperin-mediated STAT1 degradation and restricted CVB3-induced AHF. This study established the first signaling linker between CVB3 and AHF-associated cardiac electrical dysfunction, and reveals the potential of interfering peptides targeting Viperin for the treatment of CVB3-induced AHF.

柯萨奇病毒B3（CVB3）诱导的急性心力衰竭（AHF）是导致青年及中年人 cardiogenic death 的常见原因。然而，将 CVB3 与 AHF 相关联的关键分子事件至今仍鲜为人知，导致缺乏针对性的治疗策略。在本研究中，我们意外发现 Viperin 缺陷不仅不能促进 CVB3 感染，还能保护小鼠免受 CVB3 诱导的 AHF。值得注意的是，Viperin 在心脏特异性表达下可引发心脏功能障碍。在机制上，CVB3-3C 蛋白酶通过切割 UBE4A 来拯救心肌细胞中 Viperin 蛋白的表达。Viperin 随后招募并降低 STAT1 的水平，激活 SGK1-KCNQ1 信号通路，导致心脏电功能障碍和随后的 AHF。此外，我们设计了一种干扰肽 VS-IP1，该肽能够阻断 Viperin 介导的 STAT1 降解并限制 CVB3 诱导的 AHF。本研究首次建立了 CVB3 与 AHF 相关的心脏电功能障碍之间的信号传导连接，并揭示了针对 Viperin 的干扰肽在治疗 CVB3 诱导的 AHF 中的潜在应用价值。