Coronavirus Nsp5‑mediated dual‑site cleavage of GSDMA modifies its antiviral and proinflammatory functions
5 affiliations
- 1National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- 2The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- 3State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
- 4Center of Animal Laboratory, Xuzhou Medical University, Xuzhou, China
- 5Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
Abstract
Although Gasdermin A (GSDMA) drives inflammation by inducing pyroptosis, its specific role in antiviral defense remains unclear. Here we identify GSDMA as an immunomodulatory protein activated in response to coronavirus (CoV) infection. Specifically, CoV-encoded protease nsp5 cleaves GSDMA at two conserved glutamine sites, Q247 and Q187. Cleavage at Q247 liberates an active N-terminal fragment (GSDMA_1–247) that triggers pyroptosis, promotes inflammation, and restricts viral replication. In contrast, cleavage at the alternative site Q187 attenuates this function. Using Gsdma-/- mice, we show that GSDMA deficiency increases viral loads but reduces inflammation, tissue damage, and mortality upon infection. These findings suggest that disease severity is driven more by inflammation than by viral load. Our findings reveal a novel mechanism of antiviral immunity and inflammatory regulation via CoV nsp5-mediated dual cleavage of GSDMA, highlighting a potential target for combined antiviral and anti-inflammatory therapies. Author summary: Coronaviruses continue to threaten global health, as demonstrated by recent outbreaks. Gasdermin A (GSDMA) is a host protein involved in pyroptosis, which is an inflammatory cell death. In this study, we demonstrate that the coronavirus 3C-like protease cleaves GSDMA at two distinct sites, generating fragments with different functional properties. One cleavage product enhances inflammation and limits viral replication, whereas the other does not exhibit these activities. Our findings suggest that coronaviruses 3C-like proteases may regulate cleavage at these two sites to influence the relative abundance of the resulting fragments, thereby balancing antiviral defense and inflammatory responses. Using a mouse model, we further demonstrate that loss of GSDMA results in higher viral loads but reduced inflammatory pathology and improved survival. These observations indicate that disease severity may be more closely linked to the magnitude of the inflammatory response than to viral burden alone. Together, our work highlights the importance of targeting both viral replication and dysregulated inflammation in therapeutic strategies.
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BibTeX
@article{li2026coronavirus,
title = {{Coronavirus Nsp5‑mediated dual‑site cleavage of GSDMA modifies its antiviral and proinflammatory functions}},
author = {Chenyu Li and Yuxi Zhao and Yuchen Zhang and Shuai Li and Longfei Chen and Xiangfei Xu and Tong Ding and Yuanqing Wang and Xiang Gao and Zhaoyu Lin and Guanning Su and Ankang Hu and Liurong Fang and Qi Su and Quangang Chen and Yanrong Zhou and Shaobo Xiao},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014602},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014602},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Coronavirus Nsp5‑mediated dual‑site cleavage of GSDMA modifies its antiviral and proinflammatory functions
AU - Chenyu Li
AU - Yuxi Zhao
AU - Yuchen Zhang
AU - Shuai Li
AU - Longfei Chen
AU - Xiangfei Xu
AU - Tong Ding
AU - Yuanqing Wang
AU - Xiang Gao
AU - Zhaoyu Lin
AU - Guanning Su
AU - Ankang Hu
AU - Liurong Fang
AU - Qi Su
AU - Quangang Chen
AU - Yanrong Zhou
AU - Shaobo Xiao
PY - 2026
DA - 2026/09/16
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014602
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014602
AB - Although Gasdermin A (GSDMA) drives inflammation by inducing pyroptosis, its specific role in antiviral defense remains unclear. Here we identify GSDMA as an immunomodulatory protein activated in response to coronavirus (CoV) infection. Specifically, CoV-encoded protease nsp5 cleaves GSDMA at two conserved glutamine sites, Q247 and Q187. Cleavage at Q247 liberates an active N-terminal fragment (GSDMA_1–247) that triggers pyroptosis, promotes inflammation, and restricts viral replication. In contrast, cleavage at the alternative site Q187 attenuates this function. Using Gsdma-/- mice, we show that GSDMA deficiency increases viral loads but reduces inflammation, tissue damage, and mortality upon infection. These findings suggest that disease severity is driven more by inflammation than by viral load. Our findings reveal a novel mechanism of antiviral immunity and inflammatory regulation via CoV nsp5-mediated dual cleavage of GSDMA, highlighting a potential target for combined antiviral and anti-inflammatory therapies. Author summary: Coronaviruses continue to threaten global health, as demonstrated by recent outbreaks. Gasdermin A (GSDMA) is a host protein involved in pyroptosis, which is an inflammatory cell death. In this study, we demonstrate that the coronavirus 3C-like protease cleaves GSDMA at two distinct sites, generating fragments with different functional properties. One cleavage product enhances inflammation and limits viral replication, whereas the other does not exhibit these activities. Our findings suggest that coronaviruses 3C-like proteases may regulate cleavage at these two sites to influence the relative abundance of the resulting fragments, thereby balancing antiviral defense and inflammatory responses. Using a mouse model, we further demonstrate that loss of GSDMA results in higher viral loads but reduced inflammatory pathology and improved survival. These observations indicate that disease severity may be more closely linked to the magnitude of the inflammatory response than to viral burden alone. Together, our work highlights the importance of targeting both viral replication and dysregulated inflammation in therapeutic strategies.
SN - 1553-7374
ER -