Zebrafish TMEM47 is an effective blocker of IFN production during RNA and DNA virus infection.

Mitochondrial antiviral signaling protein (MAVS) and stimulator of interferon (IFN) genes (STING) are crucial factors of IFN induction in RNA and DNA viral infections. However, unrestricted IFN was harmful to the host by causing cytokine storm. Here, we report that zebrafish transmembrane protein 47 (TMEM47), an IFN-negative regulator in fish, represses IFN expression stimulated by both spring viremia of carp virus (SVCV) and cyprinid herpesvirus 2, which represent RNA and DNA viruses, respectively. The mRNA level of tmem47 was rapidly upregulated during RNA and DNA virus infection. Overexpression of TMEM47 significantly blocked SVCV- and CyHV-2-mediated IFN induction, whereas knockdown of tmem47 promoted ifn transcription under these viral infections. Furthermore, TMEM47 interacted with MAVS and STING, which are considered as key factors for IFN induction during RNA and DNA viral infection. Mechanistically, both MAVS and STING were degraded by TMEM47 in an autophagy-lysosome-dependent manner, and the autophagy factor autophagy-related gene 5 (ATG5) was essential for this process. Finally, at the cellular level, MAVS- and STING-mediated antiviral capacities were significantly suppressed by TMEM47. Taken together, our results demonstrate that zebrafish TMEM47 acts as a brake to inhibit IFN production in both RNA and DNA viral infections. IMPORTANCE Mitochondrial antiviral signaling protein (MAVS) and stimulator of interferon (IFN) genes (STING) are key adaptor proteins required for innate immune responses to RNA and DNA virus infection. Here, we show that zebrafish transmembrane protein 47 (TMEM47) plays a critical role in regulating MAVS- and STING-triggered IFN production in a negative feedback manner. TMEM47 interacted with MAVS and STING for autophagic degradation, and ATG5 was essential for this process. These findings suggest the inhibitory function of TMEM47 on MAVS- and STING-mediated signaling responses during RNA and DNA virus infection.