STING1 is essential for an RNA-virus triggered autophagy

Rui Zhang; Xiaodong Qin; Yang Yang; Xueliang Zhu; Shuaiyang Zhao; Zhixiong Zhang; Qianlong Su; Zhixun Zhao; Xiangping Yin; Xuelian Meng; Zhidong Zhang; Yanmin Li

doi:10.1080/15548627.2021.1959086

STING1 is essential for an RNA-virus triggered autophagy

Autophagy. 2022 Apr;18(4):816-828. doi: 10.1080/15548627.2021.1959086. Epub 2021 Aug 2.

Authors

Rui Zhang^{1

2}, Xiaodong Qin¹, Yang Yang¹, Xueliang Zhu¹, Shuaiyang Zhao¹, Zhixiong Zhang^{1

2}, Qianlong Su¹, Zhixun Zhao¹, Xiangping Yin¹, Xuelian Meng¹, Zhidong Zhang², Yanmin Li²

Affiliations

¹ State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, China.
² Department of preventive veterinary medicine, College of Life Science & Technology, Southwest Minzu University, Chengdu, Sichuan, China.

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.

Keywords: Autophagy; EIF2AK3; RNA virus; STING1; integrated stress response.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy* / genetics
Endoplasmic Reticulum Stress
Interferons
RNA
RNA Viruses*

Substances

RNA
Interferons

Grants and funding

This work was supported by the National Key R & D Program of China (2016YFE0204100), the National Natural Science Foundation of China (31801191), Southwest Minzu University Research Startup Funds (125900/16011211013).