{"doi":"10.1101/2023.06.02.543413","title":"HDAC4-mediated deacetylation of GSDMD prevents pyroptosis by inhibiting GSDMD ubiquitination","abstract":"Abstract Gasdermin D (GSDMD) functions as a key pyroptotic executor and induces cytokine secretion after cleavage by inflammatory caspases. However, less is known about the role of posttranslational modifications (PTMs) in GSDMD-mediated pyroptosis. Here, we report that GSDMD can be acetylated at Lysine 248 residue and the acetylation of GSDMD promotes pyroptosis. We identified histone deacetylase 4 (HDAC4) as the specific deacetylase that mediates GSDMD deacetylation and subsequent pyroptosis inhibition in vitro and in vivo . GSDMD deacetylation impairs the ubiquitination of GSDMD, for which pyroptosis is inhibited. Interestingly, the phosphorylation of HDAC4 is important for its ability of deacetylating GSDMD and suppressing GSDMD-mediated pyroptosis. The Protein phosphatase 1 (PP1) catalytic subunits (PP1α and PP1γ) mediate the dephosphorylation of HDAC4, thereby abrogating its deacetylase activity on GSDMD. Therefore, our work unravels a complex regulatory mechanism involving HDAC4, PP1 and GSDMD, and provides novel insights into the crosstalk among acetylation, ubiquitination and phosphorylation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":399726,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1175780,"name":"Xinyue Li","orcid":"0000-0003-1017-5253","position":1,"is_corresponding":false},{"id":1175781,"name":"Danyue Li","orcid":"0009-0008-1489-4988","position":2,"is_corresponding":false},{"id":1175782,"name":"Xinyu Fu","orcid":"0000-0002-1181-9981","position":3,"is_corresponding":false},{"id":1175783,"name":"Nan Chen","orcid":"0000-0001-9825-2369","position":4,"is_corresponding":false},{"id":1175784,"name":"Qian Lv","orcid":"0000-0001-6466-2108","position":5,"is_corresponding":false},{"id":1175785,"name":"Yuhua Shi","orcid":"0000-0003-4875-0719","position":6,"is_corresponding":false},{"id":1175786,"name":"Suhui He","orcid":"0009-0000-0492-5463","position":7,"is_corresponding":false},{"id":524230,"name":"Lu Dong","orcid":"0000-0002-1075-9374","position":8,"is_corresponding":false},{"id":522500,"name":"Yang Yang","orcid":"0000-0001-7432-4735","position":9,"is_corresponding":false},{"id":1175787,"name":"Fushan Shi","orcid":"0000-0002-5250-8493","position":10,"is_corresponding":false},{"id":1175779,"name":"Weilv Xu","orcid":"0009-0005-0628-1346","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:56.084411Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}