Virus infection leads to activation of the
interferon (IFN)-induced
endoribonuclease RNase L, which results in degradation of viral and cellular RNAs. Both cellular and
viral RNA cleavage products of
RNase L bind
pattern recognition receptors (
PRRs), like
retinoic acid-inducible I (Rig-I) and
melanoma differentiation-associated protein 5 (MDA5), to further amplify IFN production and
antiviral response. Although much is known about the mechanics of
ligand binding and PRR activation, how cells coordinate
RNA sensing with signaling response and
interferon production remains unclear. We show that RNA cleavage products of
RNase L activity induce the formation of
antiviral stress granules (avSGs) by regulating activation of
double-stranded RNA (dsRNA)-dependent
protein kinase R (PKR) and recruit the
antiviral proteins Rig-I, PKR, OAS, and
RNase L to avSGs. Biochemical analysis of purified avSGs showed interaction of a key stress granule
protein, G3BP1, with only PKR and Rig-I and not with OAS or
RNase L. AvSG assembly during
RNase L activation is required for IRF3-mediated IFN production, but not IFN signaling or proinflammatory
cytokine induction. Consequently, cells lacking avSG formation or
RNase L signaling produced less IFN and showed higher susceptibility during Sendai virus
infection, demonstrating the importance of avSGs in
RNase L-mediated host defense. We propose a role during
viral infection for
RNase L-cleaved RNAs in inducing avSGs containing
antiviral proteins to provide a platform for efficient interaction of
RNA ligands with
pattern recognition receptors to enhance IFN production to mount an effective
antiviral response.IMPORTANCE Double-stranded RNAs produced during
viral infections serve as
pathogen-associated molecular patterns (
PAMPs) and bind
pattern recognition receptors to stimulate IFN production.
RNase L is an IFN-regulated
endoribonuclease that is activated in virus-infected cells and cleaves single-stranded viral and cellular RNAs. The
RNase L-cleaved dsRNAs signal to Rig-like helicases to amplify IFN production. This study identifies a novel role of
antiviral stress granules induced by
RNase L as an
antiviral signaling hub to coordinate the
RNA ligands with cognate receptors to mount an effective host response during
viral infections.