Interaction of caveolin-1 with ATG12-ATG5 system suppresses autophagy in lung epithelial cells

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 306; no. 11; pp. L1016 - L1025
• Main Authors: Chen, Zhi-Hua, Cao, Jiao-Fei, Zhou, Jie-Sen, Liu, Hui, Che, Luan-Qing, Mizumura, Kenji, Li, Wen, Choi, Augustine M K, Shen, Hua-Hao
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.06.2014
• Subjects: Alveolar Epithelial Cells - physiology; Amino Acid Sequence; Animals; Autophagy; Autophagy-Related Protein 12; Autophagy-Related Protein 5; Autophagy-Related Proteins; Binding, Competitive; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caveolin 1 - genetics; Caveolin 1 - metabolism; Cell Line; Cells; Cytoplasm - metabolism; Gene Expression Regulation; Homeostasis; Humans; Lung diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mutation; Protein Binding; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Small Ubiquitin-Related Modifier Proteins - genetics; Small Ubiquitin-Related Modifier Proteins - metabolism; ATG16L; caveolin-1; lung diseases; ATG12-ATG5; autophagy
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00268.2013

Autophagy plays a pivotal role in cellular homeostasis and adaptation to adverse environments, although the regulation of this process remains incompletely understood. We have recently observed that caveolin-1 (Cav-1), a major constituent of lipid rafts on plasma membrane, can regulate autophagy in cigarette smoking-induced injury of lung epithelium, although the underlying molecular mechanisms remain incompletely understood. In the present study we found that Cav-1 interacted with and regulated the expression of ATG12-ATG5, an ubiquitin-like conjugation system crucial for autophagosome formation, in lung epithelial Beas-2B cells. Deletion of Cav-1 increased basal and starvation-induced levels of ATG12-ATG5 and autophagy. Biochemical analyses revealed that Cav-1 interacted with ATG5, ATG12, and their active complex ATG12-ATG5. Overexpression of ATG5 or ATG12 increased their interactions with Cav-1, the formation of ATG12-ATG5 conjugate, and the subsequent basal levels of autophagy but resulted in decreased interactions between Cav-1 and another molecule. Knockdown of ATG12 enhanced the ATG5-Cav-1 interaction. Mutation of the Cav-1 binding motif on ATG12 disrupted their interaction and further augmented autophagy. Cav-1 also regulated the expression of ATG16L, another autophagy protein associating with the ATG12-ATG5 conjugate during autophagosome formation. Altogether these studies clearly demonstrate that Cav-1 competitively interacts with the ATG12-ATG5 system to suppress the formation and function of the latter in lung epithelial cells, thereby providing new insights into the molecular mechanisms by which Cav-1 regulates autophagy and suggesting the important function of Cav-1 in certain lung diseases via regulation of autophagy homeostasis.