Feedback loop regulation between viperin and viral hemorrhagic septicemia virus through competing protein degradation pathways.

Viperin is an antiviral protein that exhibits a remarkably broad spectrum of antiviral activity. Viperin-like proteins are found all kingdoms of life, suggesting it is an ancient component of the innate immune system. However, viruses have developed strategies to counteract viperin's effects. Here, we describe a feedback loop between viperin and viral hemorrhagic septicemia virus (VHSV), a common fish pathogen. We show that Importance: Viral hemorrhagic septicaemia (VHS) is a contagious disease caused by the viral hemorrhagic septicaemia virus (VHSV), which poses a threat to over 80 species of marine and freshwater fish. Currently, there are no effective treatments available for this disease. Understanding the mechanisms of VHSV-host interaction is crucial for preventing viral infections. Here, we found that, as an ancient antiviral protein, viperin degrades the N and P proteins of VHSV through the autophagy pathway. Additionally, the N protein also impacts the biological functions of IRF1 and IRF9 through the ubiquitin-proteasome pathway, leading to the suppression of viperin expression. Therefore, the N protein may serve as a potential virulence factor for the development of VHSV vaccines and screening of antiviral drugs. Our research will serve as a valuable reference for the development of strategies to prevent VHSV infections.