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

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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Publication Details

Journal
Nucleic Acids Research
Published
2024-10-24
DOI
https://doi.org/10.1093/nar/gkae921
Citations
9
Primary Topic
RNA regulation and disease
Type
article
Field-Weighted Citation Impact
2.10

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article

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

Wenlong He, Gege Zhang, Chuanhong Wang, Baochao Fan et al.
9 citations
Nucleic Acids Research
RNA regulation and disease
2.10
article

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

Wenlong He, Gege Zhang, Chuanhong Wang, Baochao Fan, Yunchuan Li, Bin Li, Xuejiao Zhu, Jiali Qian, Jinzhu Zhou, Qi Peng, Mi Hu, Yupeng Li, Shiyu Liu, Xue Zhang, Kongwang He, Hong Xu, Shanshan Yang, Yongxiang Zhao, Rongli Guo, Yi-Xiang Wang, Wei Wang
article en
9 citations

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.

Nucleic Acids ResearchVol. 52(21)
Jiangsu University (CN), Nanjing Agricultural University (CN), Jiangsu Academy of Agricultural Sciences (CN), Ministère de l'Agriculture et de la Souveraineté alimentaire (FR), Ministry of Science ICT and Future Planning (KR), Yangzhou University (CN)
Jiangsu Academy of Agricultural Sciences, Jiangsu Agricultural Science and Technology Innovation Fund, National Natural Science Foundation of China, Government of Jiangsu Province, Natural Science Foundation of Jiangsu Province, National Key Research and Development Program of China
Good health and well-being
Openalex Percentile: Top 12%
RNA regulation and disease
2.10
DOIOpen Access PDFOpenAlex
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