The E3 ubiquitin ligase Fancl negatively regulates zebrafish antiviral immunity against spring viremia of carp virus.

The innate immune response serves as the first line of host defense against pathogenic infections, and its precise regulation is critical for maintaining immune homeostasis. Fanconi Anemia complementation group L (Fancl) is an E3 ubiquitin ligase that plays an essential role in zebrafish ovarian differentiation, but whether it is involved in innate immunity remains elusive. Here, we investigate the function of fancl in antiviral innate immunity using zebrafish model. We found that fancl was induced upon spring viremia of carp virus (SVCV) infection. Overexpression of fancl in cells suppressed antiviral gene expression and promoted viral replication, whereas fancl-/- zebrafish exhibited enhanced antiviral resistance with increased survival rate, higher interferon-stimulated genes expression, and reduced viral loads. Mechanistically, fancl deficiency increased Tp53 protein abundance in zebrafish following SVCV infection. Consistently, tp53-/- zebrafish exhibited impaired antiviral immunity, with increased mortality and enhanced viral proliferation, indicating that Tp53 is required for the antiviral response. Together, our findings identify fancl as a critical negative regulator of antiviral innate immunity and reveal that fancl functions through Tp53 to orchestrate antiviral innate immunity. This study also provides potential genetic insights into disease-resistant breeding in aquaculture.