Coronavirus S protein alters dsRNA accumulation and stress granule formation through regulation of ADAR1-p150 expression

  • Nucleic Acids Res. 2024 Nov 27;52(21):13174-13191. doi: 10.1093/nar/gkae921.
Baochao Fan  1  2  3  4  5 ,  Yupeng Li  1 ,  Yi Wang  1 ,  Shanshan Yang  1  2 ,  Qi Peng  1  2 ,  Jiali Qian  1  3 ,  Chuanhong Wang  1 ,  Xue Zhang  1 ,  Hong Xu  1 ,  Shiyu Liu  1  3 ,  Wenlong He  1 ,  Gege Zhang  1 ,  Xuejiao Zhu  1  2 ,  Yunchuan Li  1  2 ,  Yongxiang Zhao  1  2 ,  Mi Hu  1  2 ,  Wei Wang  1  2 ,  Jinzhu Zhou  1  2 ,  Rongli Guo  1  2 ,  Kongwang He  1  2 ,  Bin Li  1  2  3  5  6
Affiliations
  • 1. Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture; Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, 50 Zhongling Street, Nanjing 210014, China.
  • 2. Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 88 South Daxue Road, Yangzhou University, Yangzhou 225009, China.
  • 3. College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Xiaolingwei Street, Nanjing 210095, China.
  • 4. School of Life Sciences, Jiangsu University, 301 Xuefu Road, Xiangshan Street, Zhenjiang 212013, China.
  • 5. GuoTai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, 28 Xinglin Road, Taizhou 225300, China.
  • 6. School of Food and Biological Engineering, Jiangsu University, 301 Xuefu Road, Xiangshan Street, Zhenjiang 212013, China.
PMID: 39445805 DOI: 10.1093/nar/gkae921
Abstract

The precise role of the highly variable coronavirus S protein in modulating innate immune responses remains unclear. In this study, we demonstrated that the mutant strain of swine coronavirus porcine enteric diarrhea virus induced significantly lower levels of double-stranded RNA (dsRNA) accumulation, inhibited protein kinase R (PKR) activation and suppressed stress granule (SG) formation compared with the classical strain. The 29th amino acid at N-terminus of S was identified as the key functional site for regulation of SG formation, and found that mutant S inhibited PKR phosphorylation and SG formation by upregulating Adenosine Deaminase acting on RNA 1 (ADAR1)-p150. Notably, the Zα domain of ADAR1-p150 was essential for inhibiting SG formation. Upregulation of ADAR1-p150 also reduced accumulation of dsRNA depending on its RNA editing function. Virus rescue confirmed that the mutant carrying a substitution at amino acid 29 failed to induce ADAR1-p150, leading to dsRNA accumulation, PKR activation and SG formation. Interestingly, the latest severe acute respiratory syndrome coronavirus-2 strains exhibit a novel 25PPA27 deletion at N-terminus of S that was also shown to lead to altered ADAR1-p150 expression and SG inhibition. The transcription factor TCF7L2 was identified as a player in S-mediated transcriptional enhancement of ADAR1-p150. This study is the first to clarify the crucial role of N-terminus of S in immune regulation of coronaviruses.

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