USP14 promotes K63‐linked RIG‐I deubiquitination and suppresses antiviral immune responses

RIG‐I is a critical RNA virus sensor that initiates antiviral immune response through K63‐linked ubiquitination. In this study, we demonstrated USP14, a deubiquitinating enzyme, as a negative regulator in antiviral responses by directly deubiquitinating K63‐linked RIG‐I. USP14 knockdown significantly enhanced RIG‐I‐triggered type I IFN signaling and inhibited VSV replication both in mouse peritoneal macrophages and THP1 cells. USP14 overexpression in HeLa cells attenuated RIG‐I‐triggered IFN‐β expression and promoted VSV replication. Besides, USP14 specific inhibitor‐IU1 increased RIG‐I‐mediated type I IFN production and antiviral responses in vitro and in vivo. In addition, USP14 could interact with RIG‐I and remove RIG‐I K63‐linked polyubiquitination chains. This paper is the first to report that USP14 acts as a negative regulator in antiviral response through deubiquitinating K63‐linked RIG‐I. These findings provide insights into a potential new therapy targeting USP14 for RNA virus related diseases.

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