PAWR augments anti-RNA viral innate immunity by promoting the PIM2-XBP1s-RIG-I signaling axis.

PRKC Apoptosis WT1 Regulator (PAWR) has been implicated in tumorigenesis. However, its role in antiviral innate immunity remains unexplored. Here, we demonstrate that PAWR transcriptionally upregulates RIG-I expression through the transcription factor X-box binding protein 1 (XBP1). Mechanistically, PAWR potentiates the ATF6/IRE1-XBP1 pathway to upregulate spliced form XBP1 (XBP1s) and simultaneously promotes PIM2-mediated phosphorylation of XBP1s at Ser68. Activated XBP1s binds the RIG-I promoter, driving RIG-I expression and amplifying IFN-I responses during RNA virus infection. Most intriguingly, PAWR-silenced THP-1 cells and primary macrophages exhibit attenuated anti-RNA viral IFN-I responses. Pawr-deficient mice are more susceptible to RNA virus challenge. Notably, Arylquin 1, the small molecule activator of PAWR, inhibits VSV replication by boosting the RIG-I-mediated IFN-I response in a PAWR-dependent manner. Collectively, our findings highlight a critical function of PAWR in antiviral innate immunity via the PIM2-XBP1s-RIG-I signaling axis, establishing its potential as a promising therapeutic target for RNA viral infections.