Key Laboratory of Applied Technology On Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, 666 Wusu Street, Lin'an District, Hangzhou, 311300, Zhejiang Province, China.
Vet Res. 2024 Feb 27;55(1):26. doi: 10.1186/s13567-024-01282-1.
Pyroptosis is a form of programmed cell death characterized by cell swelling, pore formation in the plasma membrane, lysis, and releases of cytoplasmic contents. To date, the molecular mechanism of human and murine Gasdermin D-mediated pyroptosis have been fully investigated. However, studies focusing on molecular mechanism of bovine Gasdermin D (bGSDMD)-mediated pyroptosis and its function against pathogenic infection were unclear. In the present study, we demonstrate that bovine caspase-1 (bCaspase-1) cleaves bGSDMD at amino acid residue D277 to produce an N-terminal fragment (bGSDMD-p30) which leads to pyroptosis. The amino acid residues T238 and F239 are critical for bGSDMD-p30-mediated pyroptosis. The loop aa 278-299, L293 and A380 are the key sites for autoinhibitory structure of the full length of bGSDMD. In addition, bCaspase-3 also cleaves bGSDMD at residue Asp86 without inducing cell death. Therefore, our study provides the first detailed elucidation of the mechanism of bovine GSDMD-mediated pyroptosis. The results will establish a significant foundation for future research on the role of pyroptosis in bovine infectious diseases.
细胞焦亡是一种程序性细胞死亡形式，其特征为细胞肿胀、质膜形成孔道、裂解，并释放细胞质内容物。迄今为止，已充分研究了人类和鼠类 GSDMD 介导的细胞焦亡的分子机制。然而，针对牛 GSDMD（bGSDMD）介导的细胞焦亡的分子机制及其针对病原感染的功能的研究尚不清楚。在本研究中，我们证明牛半胱天冬氨酸蛋白酶-1（bCaspase-1）在氨基酸残基 D277 处切割 bGSDMD，产生导致细胞焦亡的 N 端片段（bGSDMD-p30）。氨基酸残基 T238 和 F239 对于 bGSDMD-p30 介导的细胞焦亡至关重要。aa278-299 环、L293 和 A380 是全长 bGSDMD 自身抑制结构的关键位点。此外，bCaspase-3 还在不诱导细胞死亡的情况下在天冬氨酸残基 86 处切割 bGSDMD。因此，本研究首次详细阐明了牛 GSDMD 介导的细胞焦亡的机制。该结果将为牛传染性疾病中细胞焦亡作用的未来研究奠定重要基础。
