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Kesireddy, V.S.* ; Chillappagari, S.* ; Ahuja, S.* ; Knudsen, L.* ; Henneke, I.* ; Graumann, J.* ; Meiners, S. ; Ochs, M.* ; Ruppert, C.* ; Korfei, M.* ; Seeger, W.* ; Mahavadi, P.*

Susceptibility of microtubule-associated protein 1 light chain 3 beta (MAP1LC3B/LC3B) knockout mice to lung injury and fibrosis.

FASEB J. 33, 12392-12408 (2019)
Publ. Version/Full Text DOI
Insufficient autophagy has been reported in idiopathic pulmonary fibrosis (IPF) lungs. Specific roles of autophagy-related proteins in lung fibrosis development remain largely unknown. Here, we investigated the role of autophagy marker protein microtubule-associated protein 1 light chain 3 beta (LC3B) in the development of lung fibrosis. LC3B(-/-) mice upon aging show smaller lamellar body profiles, increased cellularity, alveolar epithelial cell type II (AECII) apoptosis, surfactant alterations, and lysosomal and endoplasmic reticulum stress. Autophagosomal soluble N-ethylmaleimide-sensitive factor attachment protein receptor syntaxin 17 is increased in the AECII of aged LC3B(-/-) mice and patients with IPF. Proteasomal activity, however, remained unaltered in LC3B(-/- )mice. In vitro knockdown of LC3B sensitized mouse lung epithelial cells to bleomycin-induced apoptosis, but its overexpression was protective. In vivo, LC3B(-/-) mice displayed increased susceptibility to bleomycin-induced lung injury and fibrosis. We identified cathepsin A as a novel LC3B binding partner and its overexpression in vitro drives MLE12 cells to apoptosis. Additionally, cathepsin A is increased in the AECII of aged LC3B(-/-) mice and in the lungs of patients with IPF. Our study reveals that LC3B mediated autophagy plays essential roles in AECII by modulating the functions of proteins like cathepsin A and protects alveolar epithelial cells from apoptosis and subsequent lung injury and fibrosis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Alveolar Epithelial Cells ; Lamellar Bodies ; Autophagy ; Aging ; Lysosome; Idiopathic Pulmonary-fibrosis; Lamellar Bodies; Cathepsin-a; Autophagy; Cell; Stress; Homeostasis; Inhibition; Secretion; Apoptosis
ISSN (print) / ISBN 0892-6638
e-ISSN 1530-6860
Journal FASEB Journal
Quellenangaben Volume: 33, Issue: 11, Pages: 12392-12408 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Bethesda, Md.
Reviewing status Peer reviewed