{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:34:38Z","timestamp":1790948078810,"version":"4.1.0"},"reference-count":81,"publisher":"National Academy of Sciences","issue":"29","license":[{"start":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T00:00:00Z","timestamp":1720483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM127609"],"award-info":[{"award-number":["R01GM127609"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI143992"],"award-info":[{"award-number":["R01AI143992"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["P01AI141360"],"award-info":[{"award-number":["P01AI141360"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R03AI173549"],"award-info":[{"award-number":["R03AI173549"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["P01AI141360"],"award-info":[{"award-number":["P01AI141360"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["P30DK097948"],"award-info":[{"award-number":["P30DK097948"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,7,16]]},"abstract":"<jats:p>\n                    Gasdermin D (GSDMD)-mediated pyroptotic cell death drives inflammatory cytokine release and downstream immune responses upon inflammasome activation, which play important roles in host defense and inflammatory disorders. Upon activation by proteases, the GSDMD N-terminal domain (NTD) undergoes oligomerization and membrane translocation in the presence of lipids to assemble pores. Despite intensive studies, the molecular events underlying the transition of GSDMD from an autoinhibited soluble form to an oligomeric pore form inserted into the membrane remain incompletely understood. Previous work characterized\n                    <jats:italic>S<\/jats:italic>\n                    -palmitoylation for gasdermins from bacteria, fungi, invertebrates, as well as mammalian gasdermin E (GSDME). Here, we report that a conserved residue Cys191 in human GSDMD was\n                    <jats:italic>S<\/jats:italic>\n                    -palmitoylated, which promoted GSDMD-mediated pyroptosis and cytokine release. Mutation of Cys191 or treatment with palmitoyltransferase inhibitors cyano-myracrylamide (CMA) or 2-bromopalmitate (2BP) suppressed GSDMD palmitoylation, its localization to the membrane and dampened pyroptosis or IL-1\u03b2 secretion. Furthermore,\n                    <jats:italic>Gsdmd<\/jats:italic>\n                    -dependent inflammatory responses were alleviated by inhibition of palmitoylation in vivo. By contrast, coexpression of GSDMD with palmitoyltransferases enhanced pyroptotic cell death, while introduction of exogenous palmitoylation sequences fully restored pyroptotic activities to the C191A mutant, suggesting that palmitoylation-mediated membrane localization may be distinct from other molecular events such as GSDMD conformational change during pore assembly. Collectively, our study suggests that\n                    <jats:italic>S<\/jats:italic>\n                    -palmitoylation may be a shared regulatory mechanism for GSDMD and other gasdermins, which points to potential avenues for therapeutically targeting\n                    <jats:italic>S<\/jats:italic>\n                    -palmitoylation of gasdermins in inflammatory disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2400883121","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T13:43:01Z","timestamp":1720532581000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":48,"title":["Palmitoylation at a conserved cysteine residue facilitates gasdermin D-mediated pyroptosis and cytokine release"],"prefix":"10.1073","volume":"121","author":[{"given":"Zhonghua","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathology, Case Western Reserve University, Cleveland, OH 44106"},{"name":"Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4878-8103","authenticated-orcid":false,"given":"Sai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University, Cleveland, OH 44106"},{"name":"Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University, Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaylynn J.","family":"Vidmar","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University, Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3314-3505","authenticated-orcid":false,"given":"Syrena","family":"Bracey","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University, Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Li","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolic Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44196"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6884-6369","authenticated-orcid":false,"given":"Belinda","family":"Willard","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolic Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44196"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Miyagi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3923-5408","authenticated-orcid":false,"given":"Tong","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Chicago, Chicago, IL 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9616-1911","authenticated-orcid":false,"given":"Bryan 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