2. Academic Validation
  3. The SARS-CoV-2 3CL protease inhibits pyroptosis through the cleavage of gasdermin D

The SARS-CoV-2 3CL protease inhibits pyroptosis through the cleavage of gasdermin D

  • Virol Sin. 2025 Jun;40(3):324-332. doi: 10.1016/j.virs.2025.03.006.
Yecheng Zhang 1,  Xinlei Ji 2,  Dan Huang 2,  Gen Lu 3,  Xinwen Chen 4
Affiliations

Affiliations

  • 1 Department of Respiratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China.
  • 2 Guangzhou National Laboratory, Guangzhou 510005, China.
  • 3 Department of Respiratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China. Electronic address: lugen5663330@sina.com.
  • 4 Guangzhou National Laboratory, Guangzhou 510005, China. Electronic address: chen_xinwen@gzlab.ac.cn.
PMID: 40118151 DOI: 10.1016/j.virs.2025.03.006
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of novel coronavirus disease 2019, can cause acute respiratory symptoms and even death globally. However, the immune escape mechanism and viral pathogenesis remain poorly understood. Here, we report that the SARS-CoV-2 3C-like (3CL) protease specifically cleaves gasdermin D (GSDMD) at Q29 and Q193, producing two N-terminal fragments, GSDMD1-29 and GSDMD1-193. We also found that SARS-CoV-2 Infection induced the cleavage of GSDMD. Then, we demonstrated that the ability to cleave GSDMD was dependent on the protease activity of the 3CL protease. Interestingly, unlike the GSDMD1-275 fragment cleaved by Caspase-1, GSDMD1-29 and GSDMD1-193 did not trigger Pyroptosis or inhibit SARS-CoV-2 replication. Additionally, various RNA viral proteases display different preferences for cleaving GSDMD at Q29 and Q193. Our findings reveal a mechanism by which SARS-CoV-2 and Other RNA viruses inhibit Pyroptosis, highlighting the critical role of the 3CL protease in immune evasion and viral replication.

Keywords

3C-like (3CL) protease; Gasdermin D (GSDMD); Pyroptosis; SARS-CoV-2.

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