Zebrafish ZDHHC11 palmitoylates STING to potentiate antiviral immune response

In mammals, the activation of stimulator of interferon gene (STING), a pivotal adaptor protein mediating type I interferon (IFN-I) induction upon DNA virus infection, is regulated by palmitoylation. This post-translational modification is catalyzed by zinc finger DHHC domain-containing palmitoyltransferases (ZDHHCs). However, the specific palmitoyltransferases accountable for mediating STING palmitoylation remain predominantly unknown. This study demonstrated that ZDHHC11 plays a critical role by modifying STING palmitoylation and subsequently enhancing the antiviral response in zebrafish. The expression of zebrafish ZDHHC11 was found to be upregulated upon stimulation with GCRV, SVCV, B-DNA, and Z-DNA in the tested tissues or cells. Consistently, the overexpression of zebrafish ZDHHC11 led to an increase in IFN-I expression, while its knockdown resulted in a suppression of IFN-I expression. Mechanistically, ZDHHC11 specifically bound to STING at the endoplasmic reticulum (ER) and then promoted STING palmitoylation via its palmitoyltransferase activity thereby activating the STING-IRF3-mediated IFN I response. In addition, we have demonstrated that ZDHHC11 is capable of inhibiting SVCV replication both in vitro and in vivo. In conclusion, our findings revealed a novel role for ZDHHC11 in regulation of antiviral response. This implies that ZDHHC11 serves as a valuable target for modulating STING signaling and for the development of antiviral therapies.