Abstract
While the functions of STING1 (stimulator of interferon response cGAMP interactor 1) during DNA virus infection had been well documented, the roles STING1 plays during RNA viruses infection is obscure. Infection with foot-and-mouth disease virus (FMDV), a well-known picornavirus, induces endoplasmic reticulum (ER) stress response and autophagy. Here, we found that the FMDV-induced integrated stress response originates from the cellular pattern recognition receptor DDX58/RIG-I (DExD/H-box helicase 58). DDX58 transmits signals to the ER-anchored adaptor protein STING1, which specifically activates the EIF2AK3/PERK (eukaryotic translation initiation factor 2A)-dependent integrated stress response and finally leads to reticulophagy and degradation of STING1 itself. Knockdown/knockout of STING1 or EIF2AK3 suppresses FMDV genome replication and viral protein expression. Reticulophagy induction by STING1 does not require its translocation to the Golgi or IFN response activation. However, STING1 polymerization is necessary for the FMDV-induced integrated stress response and reticulophagy. Our work illustrated the signaling cascades that mediate the cellular stress response to FMDV infection and indicated that induction of autophagy in response to both DNA and RNA virus infection may be an evolutionarily conserved function of STING1. Abbreviations: ATF6: activating transcription factor 6; CGAS: cyclic GMP-AMP synthase; DDX58/RIG-I: DExD/H-box helicase 58; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 2; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; FMD: foot-and-mouth disease; FMDV: foot-and-mouth disease virus; IFIH1/MDA5: interferon induced with helicase C domain 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; RETREG1/FAM134B: reticulophagy regulator 1; STING1: stimulator of interferon response cGAMP interactor 1; TCID50: 50% tissue culture infectious dose; XBP1: X-box binding protein 1.