Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema

Proceedings of the National Academy of Sciences of the United States of America - Tập 107 Số 44 - Trang 18880-18885 - 2010
Zhi-Hua Chen1,2, Hilaire C. Lam3,1, Yang Jin1, Hong-Pyo Kim1,4, Jiaofei Cao1,2, Seon‐Jin Lee1, Emeka Ifedigbo1, Harikrishnan Parameswaran5, Stefan W. Ryter1, Augustine M.K. Choi6,1,7
1*Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
2Division of Respiratory Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou 310009, People's Republic of China;
3Cellular and Molecular Pathology Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
4School of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan, 680-749, Korea
5Department of Biomedical Engineering, Boston University, Boston, MA 02118; and
6College of Medicine, Kyung Hee University, Seoul 130-701, Korea
7Houston Methodist

Tóm tắt

Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by chronic exposure to cigarette smoke (CS), which involves airway obstruction and alveolar loss (i.e., emphysema). The mechanisms of COPD pathogenesis remain unclear. Our previous studies demonstrated elevated autophagy in human COPD lung, and as a cellular and tissue response to CS exposure in an experimental model of emphysema in vivo. We identified the autophagic protein microtubule-associated protein 1 light chain-3B (LC3B) as a positive regulator of CS-induced lung epithelial cell death. We now extend these initial observations to explore the mechanism by which LC3B mediates CS-induced apoptosis and emphysema development in vivo. Here, we observed that LC3B −/− mice had significantly decreased levels of apoptosis in the lungs after CS exposure, and displayed resistance to CS-induced airspace enlargement, relative to WT littermate mice. We found that LC3B associated with the extrinsic apoptotic factor Fas in lipid rafts in an interaction mediated by caveolin-1 (Cav-1). The siRNA-dependent knockdown of Cav-1 sensitized epithelial cells to CS-induced apoptosis, as evidenced by enhanced death-inducing signaling complex formation and caspase activation. Furthermore, Cav-1 −/− mice exhibited higher levels of autophagy and apoptosis in the lung in response to chronic CS exposure in vivo. In conclusion, we demonstrate a pivotal role for the autophagic protein LC3B in CS-induced apoptosis and emphysema, suggestive of novel therapeutic targets for COPD treatment. This study also introduces a mechanism by which LC3B, through interactions with Cav-1 and Fas, can regulate apoptosis.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 107 Số 44

18880-18885

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