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

Abstract

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 3β (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 3β (MAP1LC3B/LC3B) knockout mice to lung injury and fibrosis. FASEB J. 33, 12392–12408 (2019). www.fasebj.org