SMYD3-catalyzed dimethylation of gasdermin D at lysine 43 promotes pyroptosis and inflammatory responses
4 affiliations
- 1State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, People’s Republic of China
- 2Hubei Hongshan Laboratory, Wuhan 430070, People’s Republic of China
- 3Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266237, People’s Republic of China
- 4University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
Abstract
Gasdermin D (GSDMD), a key pyroptosis effector downstream of inflammasome activation, undergoes precise regulation by multiple posttranslational modifications. Here, we identify SMYD3, a lysine methyltransferase, as a positive regulator of GSDMD. SMYD3 interacts with GSDMD and catalyzes its dimethylation at lysine 43. This modification promotes GSDMD cleavage by caspases, leading to increased oligomerization and membrane localization of GSDMD N-terminal fragment (GSDMD-NT), which ultimately induces pyroptosis. Disrupting or inhibiting SMYD3 alleviates overactivated inflammation, thereby protecting against lipopolysaccharide-induced death in mice and zebrafish. Our findings reveal a role for SMYD3 in regulating the inflammatory response and shed light on a new mechanism that modulates GSDMD-mediated pyroptosis.
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BibTeX
@article{wang2026smyd3catalyzed,
title = {{SMYD3-catalyzed dimethylation of gasdermin D at lysine 43 promotes pyroptosis and inflammatory responses}},
author = {Zixuan Wang and Shuke Jia and Yiman Luo and Wen Liu and Xiaoli Zeng and Yuhan Xiang and Lele Yu and Hongyan Deng and Xueyi Sun and Chunchun Zhu and Wuhan Xiao and Xing Liu},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2616180123},
url = {https://doi.org/10.1073/pnas.2616180123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - SMYD3-catalyzed dimethylation of gasdermin D at lysine 43 promotes pyroptosis and inflammatory responses
AU - Zixuan Wang
AU - Shuke Jia
AU - Yiman Luo
AU - Wen Liu
AU - Xiaoli Zeng
AU - Yuhan Xiang
AU - Lele Yu
AU - Hongyan Deng
AU - Xueyi Sun
AU - Chunchun Zhu
AU - Wuhan Xiao
AU - Xing Liu
PY - 2026
DA - 2026/10/27
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2616180123
UR - https://doi.org/10.1073/pnas.2616180123
AB - Gasdermin D (GSDMD), a key pyroptosis effector downstream of inflammasome activation, undergoes precise regulation by multiple posttranslational modifications. Here, we identify SMYD3, a lysine methyltransferase, as a positive regulator of GSDMD. SMYD3 interacts with GSDMD and catalyzes its dimethylation at lysine 43. This modification promotes GSDMD cleavage by caspases, leading to increased oligomerization and membrane localization of GSDMD N-terminal fragment (GSDMD-NT), which ultimately induces pyroptosis. Disrupting or inhibiting SMYD3 alleviates overactivated inflammation, thereby protecting against lipopolysaccharide-induced death in mice and zebrafish. Our findings reveal a role for SMYD3 in regulating the inflammatory response and shed light on a new mechanism that modulates GSDMD-mediated pyroptosis.
SN - 0027-8424
SN - 1091-6490
ER -