Nucleus-encoded Factors Regulate Mitochondrial Double-stranded RNA Expression during Antiviral Response

Abstract

Endogenous double-stranded RNAs (dsRNAs) trigger innate immune response by activating pattern recognition receptors (PRRs) like PKR and MDA5. One major class of endogenous dsRNAs originates from mitochondria due to bidirectioinal transcription of the mitochondrial genome, which results in the generation of long complementary RNAs (mt-dsRNAs). Under immunogenic stress, mt-dsRNAs are released to the cytosol where they interact with PRRs and trigger antiviral response. Here, we find that mt-dsRNA level is increased by various stressors including polyinosinic:polycytidylic acid (poly I:C). Through transcriptome analysis, we identify that genes involved in the mitochondrial transport mediate such phenomenon. In partcular, we find that the mitochondrial import of SLIPR, a suppressor of mtRNA decay, is facilitated, which results in the stabilization of mt-dsRNAs and subsequent immune activation by mt-dsRNAs. Collectively, our study reveals the nuclear-mitochondrial communication and the mechanism of mt-dsRNA regulation during antiviral response.