Genetic evidence for the suppressive role of zebrafish vhl targeting mavs in antiviral innate immunity during RNA virus infection

This is the authors' abstract. We don't add key points for this paper.

The von Hippel-Lindau (VHL) tumor suppressor gene VHL is a classic tumor suppressor that has been identified in family members with clear cell renal cell carcinomas, central nervous system and retinal hemangioblastomas, phaeochromocytomas, and pancreatic neuroendocrine tumors. The well-defined function of VHL is to mediate proteasomal degradation of hydroxylated hypoxia-inducible factor α proteins, resulting in the downregulation of hypoxia-responsive gene expression. Previously, we reported that VHL inhibits antiviral signaling by targeting mitochondrial antiviral signaling protein (MAVS) for proteasomal degradation. However, due to the lack of a viable animal model, the physiological role and underlying mechanism of VHL in antiviral immunity remains to be elucidated. In this study, we found that heterozygous vhl-deficient zebrafish have normal neutrophils and no gross phenotypic alterations. However, upon spring viremia of carp virus or grass carp reovirus infection, antiviral gene expression is induced in vhl+/- zebrafish compared with wild-type zebrafish. In addition, spring viremia of carp virus replication is suppressed in vhl+/- zebrafish, owing to the enhancement of antiviral ability. Furthermore, by crossing with mavs-/- zebrafish line, we observed that disruption of mavs in vhl+/- zebrafish abrogates the viral resistance exhibited in vhl+/- zebrafish. Thus, we reveal that heterozygous vhl deficiency enhances the antiviral ability of zebrafish against RNA virus infection, and we provide genetic evidence to support that zebrafish mavs serves as a mediator for the suppressive role of vhl in antiviral innate immunity.