Fish female-biased gene cyp19a1a leads to female antiviral response attenuation between sexes by autophagic degradation of MITA

From insects to mammals, both innate and adaptive immune response are usually higher in females than in males, with the sex chromosome and hormonal differences considered the main reasons. Here, we report that zebrafish cyp19a1a (cytochrome P450, family 19, subfamily A, polypeptide 1a), an autosomal gene with female-biased expression, causes female fish to exhibit a lower antiviral response. First, we successfully constructed an infection model by intraperitoneal injection of spring viremia of carp virus (SVCV) into zebrafish (Danio rerio) and Carassius auratus herpesvirus (CaHV) in gibel carp (Carassius gibelio). Specifically, female fish were more vulnerable to viral infection than males, accompanied by a significantly weaker interferon (IFN) expression. After screening several candidates, cyp19a1a, which was highly expressed in female fish tissues, was selected for further analysis. The IFN expression and antiviral response were significantly higher in cyp19a1a(-/-) than in cyp19a1a(+/+). Further investigation of the molecular mechanism revealed that Cyp19a1a targets mediator of IRF3 activation (MITA) for autophagic degradation. Interestingly, in the absence of MITA, Cyp19a1a alone could not elicit an autophagic response. Furthermore, the autophagy factor ATG14 (autophagy-related 14) was found interacted with Cyp19a1a to either promote or attenuate Cyp19a1a-mediated MITA degradation by either being overexpressed or knocked down, respectively. At the cellular level, both the normal and MITA-enhanced cellular antiviral responses were diminished by Cyp19a1a. These findings demonstrated a sex difference in the antiviral response based on a regulation mechanism controlled by a female-biased gene besides sex chromosome and hormonal differences, supplying the current understanding of sex differences in fish. Author summarySex chromosome and hormonal differences are considered as the crucial mechanisms of sexual difference in antiviral response. In this study, we report that the fish autosomal gene with female-biased expression cyp19a1a, leads to a weaker antiviral response in female fish. First, female fish were vulnerable than males when infected with virus, and with a lower IFN expression. cyp19a1a was evoked by viral stimulation and highly expressed in female fish tissues. In cyp19a1a(-/-), the IFN response and antiviral capacity were notably higher than that in cyp19a1a(+/+). Subsequently, Cyp19a1a was interacted with MITA for autophagic degradation, and Cyp19a1a could not lead to an autophagic response in the absence of MITA, in this process, ATG14 was identified associated with Cyp19a1a to promote MITA degradation. These results demonstrated that the autosomal and female-biased gene Cyp19a1a was an IFN negative regulator by mediating MITA autophagic degradation, extending the understanding of sex differences in vertebrates besides sex chromosome and hormonal differences.

Automated summary

From insects to mammals, females generally have higher innate and adaptive immune response than males. This study investigates the role of the autosomal gene cyp19a1a in the antiviral response of zebrafish. Results show that females with high expression of cyp19a1a exhibit a weaker antiviral response, and this gene mediates autophagic degradation of MITA to suppress interferon expression. These findings broaden our understanding of sex differences in the immune response.