NLRX1 promotes immediate IRF1-directed antiviral responses by limiting dsRNA-activated PKR translational inhibition

NLRX1 is unique among nucleotide-binding domain and leucine-rich repeat (NLR) proteins in its mitochondrial localization and capacity to negatively regulate MAVS- and STING-dependent antiviral innate immunity. However, some studies suggest a positive regulatory role for NLRX1 in inducing antiviral responses. We show that NLRX1 exerts opposing regulatory effects on virus activation of the transcription factors IRF1 and IRF3, potentially explaining these contradictory results. Whereas NLRX1 suppresses MAVS-mediated IRF3 activation, NLRX1 conversely facilitates virus-induced increases in IRF1 expression, thereby enhancing control of virus infection. NLRX1 has a minimal effect on NF-κB-mediated IRF1 transcription, and regulates IRF1 abundance post-transcriptionally by preventing translational shutdown mediated by the dsRNA-activated protein kinase PKR, thereby allowing virus-induced increases in IRF1 protein abundance.