Stearoyl-CoA desaturase 1 regulates antiviral innate immunity in zebrafish via PPARα-IRF3 axis.

Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting enzyme that catalyzes the desaturation of saturated fatty acids to monounsaturated fatty acids. Although lipid metabolism is increasingly recognized to influence antiviral innate immunity, the role of SCD1 in host defense, particularly in teleost fish, has not been fully explored. Here, we show that viral infection markedly suppresses SCD1 expression in zebrafish. Overexpression of zebrafish SCD1 significantly suppresses antiviral gene expression and enhances viral replication. Pharmacological inhibition of SCD1 desaturase activity enhances antiviral gene expression, reduces viral replication, and protects zebrafish larvae from viral lethality, indicating that SCD1 suppresses antiviral immunity in an enzymatic activity-dependent manner. Mechanistically, palmitic acid (PA), the saturated fatty acid substrate of SCD1, acts as a potent enhancer of antiviral innate immunity. PA treatment upregulates antiviral gene expression in vivo and in vitro, and restricts viral replication in ZFL cells. We demonstrate that PA exerts its immunostimulatory effects by inhibiting the two zebrafish isoforms of peroxisome proliferator-activated receptor α, PPARαa and PPARαb, as overexpression of either isoform attenuates PA-induced antiviral responses while a PPARα antagonist mimics the effects of PA. Furthermore, we show that PPARαa and PPARαb physically interact with interferon regulatory factor 3 (IRF3) and suppress IRF3-induced antiviral gene expression, thereby inhibiting type I interferon signaling. Collectively, our findings establish an SCD1-PA-PPARα-IRF3 regulatory axis in which SCD1 consumes its substrate PA to sustain PPARα-mediated negative regulation of IRF3-dependent antiviral gene expression, thereby restraining antiviral innate immunity.