A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis
Author
Takezaki, AkioTsukumo, Shin-Ichi
Setoguchi, Yasuhiro
Ledford, Julie G
Goto, Hisatsugu
Hosomichi, Kazuyoshi
Uehara, Hisanori
Nishioka, Yasuhiko
Yasutomo, Koji
Affiliation
Univ Arizona, Dept Cellular & Mol MedIssue Date
2019-12
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ROCKEFELLER UNIV PRESSCitation
Akio Takezaki, Shin-ichi Tsukumo, Yasuhiro Setoguchi, Julie G. Ledford, Hisatsugu Goto, Kazuyoshi Hosomichi, Hisanori Uehara, Yasuhiko Nishioka, Koji Yasutomo; A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis. J Exp Med 2 December 2019; 216 (12): 2724–2735. doi: https://doi.org/10.1084/jem.20182351Journal
JOURNAL OF EXPERIMENTAL MEDICINERights
© 2019 Takezaki et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by scattered fibrotic lesions in the lungs. The pathogenesis and genetic basis of IPF remain poorly understood. Here, we show that a homozygous missense mutation in SFTPA1 caused IPF in a consanguineous Japanese family. The mutation in SFTPA1 disturbed the secretion of SFTPA1 protein. Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection. Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type II (AEII) cells with phosphorylation of IRE1α leading to JNK-mediated up-regulation of Ripk3. The inhibition of JNK ameliorated pulmonary fibrosis in Sftpa1-KI mice, and overexpression of Ripk3 in Sftpa1-KI mice treated with a JNK inhibitor worsened pulmonary fibrosis. These findings provide new insight into the mechanisms of IPF in which a mutation in SFTPA1 promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3, highlighting the necroptosis pathway as a therapeutic target for IPF.ISSN
0022-1007EISSN
1540-9538PubMed ID
31601679Version
Final published versionae974a485f413a2113503eed53cd6c53
10.1084/jem.20182351
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