Cyprinid fish ubiquitin-specific protease 18 (USP18) downregulates the basal and induced interferon expression

In mammals, USP18 (ubiquitin-specific protease 18) specifically inhibits the expression of interferon (IFN)-stimulated genes (ISGs) by targeting IFN receptors to impair the Jak-Stat pathway. Previously we confirmed the conserved inhibitory function of crucian carp USP18. Here, we reported that zebrafish USP18 is an inhibitor of the basal and induced IFN signaling by overexpression and knockout strategies. Overexpression assays revealed that zebrafish USP18 inhibited the expression of either cellular ISGs or cellular IFN by virus infection, because fish type I IFN genes are typical ISGs and could be transcriptionally induced by themselves through the Jak-Stat pathway, which is different from mammalian type I IFN genes. Strikingly, knockout of USP18 resulted in enhanced expression of cellular IFN and ISGs both at steady states and under virus infection, thereby conferring enhanced resistance to virus infection in fish cells. Consistently, USP18 was abundantly transcribed in zebrafish tissues at steady states, and was markedly induced by virus infection, indicating that zebrafish USP18 plays a role at steady states and under virus infection. Our results unravel that cyprinid fish USP18 is a key homeostatic regulator to shape the basal and the induced IFN signaling.