{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T11:06:25Z","timestamp":1775905585209,"version":"3.50.1"},"reference-count":65,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"888","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2025,5,27]]},"abstract":"<jats:p>\n            The transcriptional regulators SMAD2 and SMAD3 share the same primary signaling pathway in response to the cytokine TGF\u03b2. However, whereas SMAD2 stimulates the differentiation of naive CD4\n            <jats:sup>+<\/jats:sup>\n            T cells into proinflammatory T helper 17 cells (T\n            <jats:sub>H<\/jats:sub>\n            17 cells), SMAD3 stimulates the differentiation of anti-inflammatory regulatory T cells (T\n            <jats:sub>reg<\/jats:sub>\n            cells). Here, we report a dynamic SMAD2-specific posttranslational modification important for T\n            <jats:sub>H<\/jats:sub>\n            17 cell differentiation. SMAD2, but not SMAD3, was reversibly S-palmitoylated at cysteine-41 and cysteine-81 by the palmitoyltransferase DHHC7 and depalmitoylated by the acyl protein thioesterase APT2. As a result, SMAD2 was recruited to intracellular membranes where its linker region was phosphorylated, leading to its interaction with the transcriptional regulator STAT3. Nuclear translocation of the SMAD2-STAT3 complex induced the expression of their target genes that promoted T\n            <jats:sub>H<\/jats:sub>\n            17 cell differentiation. Perturbation of SMAD2-STAT3 binding by inhibiting the palmitoylation-depalmitoylation cycle suppressed T\n            <jats:sub>H<\/jats:sub>\n            17 cell differentiation and reduced disease severity in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS). Thus, the S-palmitoylation\u2013depalmitoylation cycle mediated by DHHC7 and APT2 specifically regulates SMAD2, providing insights into the functional differences between SMAD2 and SMAD3 and the distinct role of SMAD2 in T\n            <jats:sub>H<\/jats:sub>\n            17 cell differentiation. The findings further highlight DHHC7 and APT2 as potential therapeutic targets for the treatment of T\n            <jats:sub>H<\/jats:sub>\n            17 cell\u2013mediated inflammatory diseases, including MS.\n          <\/jats:p>","DOI":"10.1126\/scisignal.adr2008","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T17:58:13Z","timestamp":1748368693000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["SMAD2 S-palmitoylation promotes its linker region phosphorylation and T\n            <sub>H<\/sub>\n            17 cell differentiation in a mouse model of multiple sclerosis"],"prefix":"10.1126","volume":"18","author":[{"given":"Mingming","family":"Zhang","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA."},{"name":"Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7896-4625","authenticated-orcid":true,"given":"Tao","family":"Yu","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA."},{"name":"Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0405-5686","authenticated-orcid":true,"given":"Yinong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, 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