African swine fever virus cysteine protease pS273R inhibits pyroptosis by noncanonically cleaving gasdermin D

Gaihong Zhao; Tingting Li; Xuemin Liu; Taoqing Zhang; Zhaoxia Zhang; Li Kang; Jie Song; Shijun Zhou; Xin Chen; Xiao Wang; Jiangnan Li; Li Huang; Changyao Li; Zhigao Bu; Jun Zheng; Changjiang Weng

doi:10.1016/j.jbc.2021.101480

African swine fever virus cysteine protease pS273R inhibits pyroptosis by noncanonically cleaving gasdermin D

J Biol Chem. 2022 Jan;298(1):101480. doi: 10.1016/j.jbc.2021.101480. Epub 2021 Dec 8.

Authors

Gaihong Zhao¹, Tingting Li¹, Xuemin Liu¹, Taoqing Zhang¹, Zhaoxia Zhang¹, Li Kang¹, Jie Song¹, Shijun Zhou¹, Xin Chen¹, Xiao Wang¹, Jiangnan Li¹, Li Huang¹, Changyao Li¹, Zhigao Bu¹, Jun Zheng², Changjiang Weng³

Affiliations

¹ Division of Fundamental Immunology, National African Swine Fever Para-Reference Laboratory, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Harbin, China.
² Division of Fundamental Immunology, National African Swine Fever Para-Reference Laboratory, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Harbin, China. Electronic address: zhengjun01@caas.cn.
³ Division of Fundamental Immunology, National African Swine Fever Para-Reference Laboratory, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Harbin, China. Electronic address: wengchangjiang@caas.cn.

Abstract

African swine fever (ASF) is a viral hemorrhagic disease that affects domestic pigs and wild boar and is caused by the African swine fever virus (ASFV). The ASFV virion contains a long double-stranded DNA genome, which encodes more than 150 proteins. However, the immune escape mechanism and pathogenesis of ASFV remain poorly understood. Here, we report that the pyroptosis execution protein gasdermin D (GSDMD) is a new binding partner of ASFV-encoded protein S273R (pS273R), which belongs to the SUMO-1 cysteine protease family. Further experiments demonstrated that ASFV pS273R-cleaved swine GSDMD in a manner dependent on its protease activity. ASFV pS273R specifically cleaved GSDMD at G107-A108 to produce a shorter N-terminal fragment of GSDMD consisting of residues 1 to 107 (GSDMD-N_1-107). Interestingly, unlike the effect of GSDMD-N_1-279 fragment produced by caspase-1-mediated cleavage, the assay of LDH release, cell viability, and virus replication showed that GSDMD-N_1-107 did not trigger pyroptosis or inhibit ASFV replication. Our findings reveal a previously unrecognized mechanism involved in the inhibition of ASFV infection-induced pyroptosis, which highlights an important function of pS273R in inflammatory responses and ASFV replication.

Keywords: African swine fever virus; gasdermin D; pS273R; pyroptosis; viral replication.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

African Swine Fever Virus* / enzymology
African Swine Fever Virus* / metabolism
African Swine Fever* / virology
Animals
Cysteine Proteases* / metabolism
Phosphate-Binding Proteins* / metabolism
Pore Forming Cytotoxic Proteins* / metabolism
Pyroptosis
Sus scrofa
Swine
Viral Proteins* / metabolism

Substances

Phosphate-Binding Proteins
Pore Forming Cytotoxic Proteins
Viral Proteins
Cysteine Proteases