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Retinoic acid-inducible gene I (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 vesicular stomatitis virus (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 removeRIG-I K63-linked polyubiquitination chains. This article 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.Keywords: Deubiquitination r RIG-I-like receptors r RNA virus sensor r USP14 r Vesicular stomatitis virus (VSV) Additional supporting information may be found online in the Supporting Information section at the end of the article.

Inflammation causes many diseases that are serious threats to human health. However, the molecular mechanisms underlying regulation of inflammation and inflammasome activation are not fully understood which has delayed the discovery of new anti-inflammatory drugs of urgent clinic need. Here, we found that the natural compound Teuvincenone F, which was isolated and purified from the stems and leaves of Premna szemaoensis, could significantly inhibit lipopolysaccharide (LPS)–induced pro-inflammatory cytokines production and NLRP3 inflammasome activation. Our results showed that Teuvincenone F attenuated K63-linked ubiquitination of NF-κB-essential modulator (NEMO, also known as IKKγ) to suppress LPS-induced phosphorylation of NF-κB, and inhibited mRNA expression of IL-1β, IL-6, TNF-α, and NLRP3. In addition, we found that decreased NLRP3 expression by Teuvincenone F suppressed NLRP3 inflammasome activation and IL-1β/IL-18 maturation. In vivo, we revealed that Teuvincenone F treatment relieved LPS-induced inflammation. In conclusion, Teuvincenone F is a highly effective natural compound to suppress LPS-induced inflammation by attenuating K63-linked ubiquitination of NEMO, highlighting that Teuvincenone F may be a potential new anti-inflammatory drug for the treatment of inflammatory and NLRP3 inflammasome-driven diseases.