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    A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis

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    Author
    Takezaki, Akio
    Tsukumo, Shin-Ichi
    Setoguchi, Yasuhiro
    Ledford, Julie G
    Goto, Hisatsugu
    Hosomichi, Kazuyoshi
    Uehara, Hisanori
    Nishioka, Yasuhiko
    Yasutomo, Koji
    Affiliation
    Univ Arizona, Dept Cellular & Mol Med
    Issue Date
    2019-12
    
    Metadata
    Show full item record
    Publisher
    ROCKEFELLER UNIV PRESS
    Citation
    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.20182351
    Journal
    JOURNAL OF EXPERIMENTAL MEDICINE
    Rights
    © 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
    0022-1007
    EISSN
    1540-9538
    PubMed ID
    31601679
    DOI
    10.1084/jem.20182351
    Version
    Final published version
    ae974a485f413a2113503eed53cd6c53
    10.1084/jem.20182351
    Scopus Count
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    UA Faculty Publications

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