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

Yecheng Zhang; Xinlei Ji; Dan Huang; Gen Lu; Xinwen Chen

doi:10.1016/j.virs.2025.03.006

June 2025

. doi: 10.1016/j.virs.2025.03.006

Citation: Yecheng Zhang, Xinlei Ji, Dan Huang, Gen Lu, Xinwen Chen. The SARS-CoV-2 3CL protease inhibits pyroptosis through the cleavage of gasdermin D .VIROLOGICA SINICA, 2025, 40(3) : 324-332. http://dx.doi.org/10.1016/j.virs.2025.03.006

SARS-CoV-2的3CL蛋白酶通过切割gasdermin D来抑制细胞焦亡

张业成 ^a ,
季鑫磊 ^b ,
黄丹 ^b ,
卢根 ^a,, ,
陈新文 ^b,,

a 广州医科大学附属广州妇女儿童医疗中心呼吸科, 中国广东省广州市 510623;
b 广州实验室, 中国广东省广州市 510005

通讯作者： 卢根, lugen5663330@sina.com; 陈新文, chen_xinwen@gzlab.ac.cn
收稿日期： 2024-11-07
录用日期： 2025-03-17

摘要

冠状病毒3CL蛋白酶是一种高度保守的关键酶，其在病毒生命周期中通过精准切割多聚蛋白促进病毒复制。除水解病毒蛋白外，3CL蛋白酶还通过与宿主细胞蛋白的复杂相互作用参与转录、翻译及核质运输等关键生物学过程，系统劫持细胞机制以增强病毒复制能力；其次，3CL蛋白酶破坏宿主天然免疫信号通路，抑制干扰素活性并切割抗病毒蛋白，抑制宿主免疫应答；再次，3CL蛋白酶可动态调节细胞焦亡与凋亡等程序性死亡通路，并通过干扰自噬机制及抑制应激颗粒形成等策略重塑细胞稳态，从而维持病毒持续性感染并加剧病理损伤。本综述系统阐述3CL蛋白酶介导病毒-宿主互作的分子机制，揭示其在冠状病毒致病过程中的核心调控作用，为开发新型靶向治疗策略提供理论依据。
- SARS-CoV-2
- , 3C样（3CL）蛋白酶
- , Gasdermin D（GSDMD）
- , 细胞焦亡

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

Yecheng Zhang ^a ,
Xinlei Ji ^b ,
Dan Huang ^b ,
Gen Lu ^a,, ,
Xinwen Chen ^b,,

a. Department of Respiratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China;
b. Guangzhou National Laboratory, Guangzhou 510005, China

Corresponding author: Gen Lu, lugen5663330@sina.com Xinwen Chen, chen_xinwen@gzlab.ac.cn
Received Date: 07 November 2024
Accepted Date: 17 March 2025

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, GSDMD_1-29 and GSDMD_1-193. 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 GSDMD_1-275 fragment cleaved by caspase-1, GSDMD_1-29 and GSDMD_1-193 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.
- SARS-CoV-2
- , 3C-like (3CL) protease
- , Gasdermin D (GSDMD)
- , Pyroptosis

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