African swine fever virus cysteine protease pS273R inhibits pyroptosis by noncanonically cleaving gasdermin D
Gaihong Zhao, Tingting Li, Xuemin Liu, Taoqing Zhang, Zhaoxia Zhang, Kang Li, Jie Song, Shijun Zhou, Xin Chen, Xiao Wang, Jiangnan Li, Li Huang, Changyao Li, Zhigao Bu, Jun Zheng, Changjiang Weng
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.