Viperin Mediates Acute Heart Failure Induced by Coxsackievirus B3

Coxsackievirus B3 (CVB3) infection can induce acute heart failure (AHF) that is a progressive clinical syndrome. However, the key molecular events linking CVB3 to AHF remain largely unknown. Here, we reveal that Viperin is crucial to mediate CVB3-induced AHF. Viperin deficiency protects mice from CVB3-induced AHF, while cardiac-specific expression of Viperin induces cardiac dysfunction. Further studies showed an intriguing mechanism: CVB3-encoded 3C protease lowers UBE4A levels to rescue Viperin protein expression in cardiomyocytes, while Viperin can recruit STAT1 to protect itself from UBE4A-mediated degradation, which however results in STAT1 degradation by UBE4A. Subsequently, STAT1 reduction in cardiomyocytes activates SGK1 signaling and eventually mediates AHF. Moreover, we designed an interfering peptide VS-IP1, which blocks Viperin-mediated STAT1 degradation and restricts CVB3-induced AHF. This study identifies a previously unknown function of Viperin as a key molecule of CVB3-induced AHF, and importantly demonstrates the potential of interfering peptides for AHF treatment.