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How K16 impacts these disorders at a molecular level is poorly understood. Here we report that K16 spatially restricts type I interferon (IFN) signaling and innate immunity in palmoplantar keratoderma (PPK) lesions in PC patients, imiquimod- and phorbol ester-induced models of sterile inflammation in mouse skin, and poly(I:C)-treated human keratinocytes\n                  <jats:italic>ex vivo<\/jats:italic>\n                  . Mechanistically, K16 interacts with effectors of the RIG-I-like receptor (RLR) pathway, including 14-3-3\u025b, and inhibits the 14-3-3\u025b:RIG-I interaction upstream of IFN activation. Topical application of the JAK inhibitor Ruxolitinib reduces the severity of PC-PPK-like lesions in\n                  <jats:italic>Krt16 null<\/jats:italic>\n                  mice. These findings uncover a new paradigm for keratin-dependent regulation of innate immunity and suggest a new approach to PC treatment.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>\n                    <jats:italic>KRT16<\/jats:italic>\n                    negatively regulates type I interferon signaling and innate immune responses in the skin, offering insight into the pathophysiology of inflammatory skin diseases including pachyonychia congenita, psoriasis and others.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.12.27.630544","type":"posted-content","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T08:30:14Z","timestamp":1735547414000},"source":"Crossref","is-referenced-by-count":3,"title":["Keratin 16 spatially inhibits type I interferon responses in stressed and diseased skin"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-3707","authenticated-orcid":false,"given":"Erez","family":"Cohen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonal","family":"Ghodke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Orosco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dajia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig N.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaylee","family":"Steen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mrinal K.","family":"Sarkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5157-8780","authenticated-orcid":false,"given":"Nurhan","family":"\u00d6zl\u00fc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lam C","family":"Tsoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann E.","family":"Gudjonsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Marchal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Hovnanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1518-1452","authenticated-orcid":false,"given":"Carole A.","family":"Parent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0680-2373","authenticated-orcid":false,"given":"Pierre A.","family":"Coulombe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025111403150606000_2024.12.27.630544v2.1","doi-asserted-by":"crossref","unstructured":"P. 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