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 3beta (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.-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 3beta (MAP1LC3B/LC3B) knockout mice to lung injury and fibrosis.
- 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.
Keywords
- aging
- alveolar epithelial cells
- autophagy
- lamellar bodies
- lysosome
