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Adv."],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:p>Loss of SHARPIN, a component of the linear ubiquitin chain assembly complex (LUBAC), causes systemic inflammation including the accumulation of eosinophils across multiple tissues in mice. However, the mechanisms by which SHARPIN regulates type 2 inflammation remain unclear. Here, we found that SHARPIN deficiency resulted in increased numbers of type 2 innate lymphoid cells (ILC2s) in the lung and other tissues via a cell-extrinsic mechanism. SHARPIN loss enhanced interleukin-33 (IL-33) production by lung stromal cells in vivo and in vitro, thereby promoting ILC2 proliferation. Mechanistically, SHARPIN directly bound IL-33 through its Pleckstrin homology-linker region and restrained IL-33 release independently of its ubiquitination. Combined deficiency of SHARPIN and IL-33 completely reversed ILC2 increase and lung inflammation, but not stromal cell death. Our study reveals a non-canonical, ubiquitin-independent function of SHARPIN as a gatekeeper of IL-33-driven type 2 inflammation.<\/jats:p>","DOI":"10.1126\/sciadv.aea2388","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:58:31Z","timestamp":1787939911000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["SHARPIN restrains IL-33 release by stromal cells to control ILC2 inflammation"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1298-5006","authenticated-orcid":true,"given":"Peng","family":"Zeng","sequence":"first","affiliation":[{"name":"Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-3102","authenticated-orcid":true,"given":"Xin","family":"Mao","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9069-3773","authenticated-orcid":true,"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0140-4635","authenticated-orcid":true,"given":"Zhiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, 100084, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6907-2833","authenticated-orcid":true,"given":"Qian","family":"Li","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0996-7109","authenticated-orcid":true,"given":"Yun-Cai","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09814"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0064-8"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09815"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09816"},{"key":"e_1_3_2_6_2","first-page":"972","article-title":"A spontaneous mutation characterized by chronic proliferative dermatitis in C57BL mice","volume":"143","author":"HogenEsch H.","year":"1993","unstructured":"H. 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