Research
| Title： | Genetic evidence for the suppressive role of zebrafish vhl targeting mavs in antiviral innate immunity during RNA virus infection |
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| First author： | Sun, Xueyi; Liu, Wen; Zhu, Chunchun; Wang, Zixuan; Deng, Hongyan; Liao, Qian; Xiao, Wuhan; Liu, Xing |
| Journal： | JOURNAL OF IMMUNOLOGY |
| Years： | 2025 |
| DOI： | 10.1093/jimmun/vkae017 |
| Abstract： | 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 alpha 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. |
