Crosstalk of HDAC4, PP1, and GSDMD in controlling pyroptosis

Gasdermin D (GSDMD) functions as a pivotal executor of pyroptosis, eliciting cytokine secretion following cleavage by inflammatory caspases. However, the role of posttranslational modifications (PTMs) in GSDMD-mediated pyroptosis remains largely unexplored. In this study, we demonstrate that GSDMD c...

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Published in:Cell death & disease 2024-02, Vol.15 (2), p.115-115, Article 115
Main Authors: Xu, Weilv, Jin, Qiao, Li, Xinyue, Li, Danyue, Fu, Xinyu, Chen, Nan, Lv, Qian, Shi, Yuhua, He, Suhui, Dong, Lu, Yang, Yang, Yan, Yuqi, Shi, Fushan
Format: Article
Language:English
Subjects:
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Acetylation
Antibodies
Biochemistry
Biomedical and Life Sciences
Catalytic subunits
Cell Biology
Cell Culture
Cell death
Deacetylation
Dephosphorylation
Histone deacetylase
Immunology
Inflammation
Life Sciences
Phosphoprotein phosphatase
Phosphorylation
Protein phosphatase
Pyroptosis
Ubiquitination
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Summary:Gasdermin D (GSDMD) functions as a pivotal executor of pyroptosis, eliciting cytokine secretion following cleavage by inflammatory caspases. However, the role of posttranslational modifications (PTMs) in GSDMD-mediated pyroptosis remains largely unexplored. In this study, we demonstrate that GSDMD can undergo acetylation at the Lysine 248 residue, and this acetylation enhances pyroptosis. We identify histone deacetylase 4 (HDAC4) as the specific deacetylase responsible for mediating GSDMD deacetylation, leading to the inhibition of pyroptosis both in vitro and in vivo. Deacetylation of GSDMD impairs its ubiquitination, resulting in the inhibition of pyroptosis. Intriguingly, phosphorylation of HDAC4 emerges as a critical regulatory mechanism promoting its ability to deacetylate GSDMD and suppress GSDMD-mediated pyroptosis. Additionally, we implicate Protein phosphatase 1 (PP1) catalytic subunits (PP1α and PP1γ) in the dephosphorylation of HDAC4, thereby nullifying its deacetylase activity on GSDMD. This study reveals a complex regulatory network involving HDAC4, PP1, and GSDMD. These findings provide valuable insights into the interplay among acetylation, ubiquitination, and phosphorylation in the regulation of pyroptosis, offering potential targets for further investigation in the field of inflammatory cell death.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-024-06505-z