SLIRP amplifies antiviral signaling via stabilizing mitochondrial double-stranded RNAs

Abstract

Endogenous double-stranded RNAs (dsRNAs) trigger innate immune responses by activating pattern recognition receptors (PRRs) like PKR and MDA5. One class of endogenous dsRNAs originates from mitochondria due to bidirectional transcription of the mitochondrial genome, which results in the generation of long complementary RNAs (mt-dsRNAs). Here, we find that under immunogenic stress, mt-dsRNAs are released to the cytosol where they interact with PRRs and trigger the antiviral response. Through transcriptome analysis, we identify that genes involved in the mitochondrial transport such as PIN1 and TOMM40 mediate such phenomenon. In particular, we find that the mitochondrial import of SLIRP, a suppressor of mtRNA decay, is facilitated, which results in the stabilization of mt-dsRNAs and subsequent amplification of antiviral signaling via mt-dsRNAs. Importantly, downregulation of SLIRP significantly decreases the interferon response to immunogenic stressors. Collectively, our study reveals the nuclear-mitochondrial communication and the mechanism of mt-dsRNA regulation during antiviral response.