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Here, we reported that alveolar epithelial type-II cells (AT II) play important roles in pathological process of pulmonary fibrosis. Through iTRAQ (isobaric tagging for relative and absolute quantification) quantitative proteomics, TSSK4 was identified to be upregulated in bleomycin-induced fibrotic mice model, which was further confirmed in clinical IPF patients\u2019 tissue specimens. TSSK4 is a germ-related protein, but its expression in other tissues and the association with other diseases are not reported. Immunofluorescence staining showed that TSSK4 selectively expressed in AT-II cells, which are essential for inflammation-induced AT-II loss during fibrosis. Luciferase assay and other molecular biological experiments proved that TSSK4 expression is regulated by TNF-\u03b1-mediated NF-\u03baB signaling. The TSSK4 kinase activity is found to be closely related to the function of HSP90-AKT pathway that TSSK4 can phosphorylate its substrate HSP90\u03b2 on serine 255, to inhibit the ATPase activity of HSP90\u03b2 and reduce its molecular chaperone function on AKT. Under this condition, kinase activity of AKT is diminished to interfere its survival function, subsequently facilitating AT-II cellular apoptosis through the mitochondrial death machinery. Our findings highlight the importance of TSSK4 in regulating pulmonary fibrosis by facilitating AT-II loss through HSP90-AKT signaling, all of which suggest TSSK4 and the regulating mechanism as attractive targets for the clinical intervention of pulmonary injury and fibrosis.<\/jats:p>","DOI":"10.1038\/s41419-021-04232-3","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T09:03:17Z","timestamp":1669971797000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["TSSK4 upregulation in alveolar epithelial type-II cells facilitates pulmonary fibrosis through HSP90-AKT signaling restriction and AT-II apoptosis"],"prefix":"10.1038","volume":"12","author":[{"given":"Huifang","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andong","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honglv","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huancheng","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieying","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoling","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjuan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changxing","family":"Ou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailin","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2040-5964","authenticated-orcid":false,"given":"Jie","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"4232_CR1","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.1016\/S0140-6736(17)30866-8","volume":"389","author":"L Richeldi","year":"2017","unstructured":"Richeldi L, Collard HR, Jones MG. 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