title: Interaction of caveolin-1 with ATG12-ATG5 system suppresses autophagy in lung epithelial cells.
abstract: 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.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China;
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: Zhejiang University Hospital, Hangzhou, China;
authors.forename: Jiao-Fei
authors.initials: JF
authors.lastname: Cao
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China;
authors.forename: Jie-Sen
authors.initials: JS
authors.lastname: Zhou
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China;
authors.forename: Luan-Qing
authors.initials: LQ
authors.lastname: Che
authors.affiliation: Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizumura
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China;
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; State Key Laboratory of Respiratory Diseases, Guangzhou, China huahaoshen@163.com.
authors.forename: Hua-Hao
authors.initials: HH
authors.lastname: Shen
mesh_terms: D056809:Alveolar Epithelial Cells / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C466624:ATG12 protein, human; C518959:ATG16L1 protein, human; C502778:ATG5 protein, human; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D051242:Caveolin 1; D008869:Microtubule-Associated Proteins; D025841:Small Ubiquitin-Related Modifier Proteins
keywords: ATG12-ATG5; ATG16L; autophagy; caveolin-1; lung diseases
references.citation: Am J Physiol Lung Cell Mol Physiol. 2012 Nov 1;303(9):L748-57
references.pmid: 22983353
references.citation: Cell Death Dis. 2011 May 19;2:e159
references.pmid: 21593791
references.citation: Mol Cell. 2010 Oct 22;40(2):280-93
references.pmid: 20965422
references.citation: Am J Respir Cell Mol Biol. 2008 Aug;39(2):171-9
references.pmid: 18323531
references.citation: Cell Struct Funct. 2002 Dec;27(6):421-9
references.pmid: 12576635
references.citation: Dev Cell. 2004 Apr;6(4):463-77
references.pmid: 15068787
references.citation: Cell Cycle. 2011 Jun 1;10(11):1784-93
references.pmid: 21566463
references.citation: Cardiovasc Res. 2010 May 1;86(2):219-25
references.pmid: 20202978
references.citation: J Immunol. 2009 Mar 15;182(6):3809-18
references.pmid: 19265160
references.citation: J Biol Chem. 1997 Mar 7;272(10):6525-33
references.pmid: 9045678
references.citation: PLoS One. 2008 Oct 02;3(10):e3316
references.pmid: 18830406
references.citation: J Biol Chem. 2007 Dec 28;282(52):37298-302
references.pmid: 17986448
references.citation: Annu Rev Genet. 2009;43:67-93
references.pmid: 19653858
references.citation: Science. 2010 Dec 3;330(6009):1344-8
references.pmid: 21127245
references.citation: Autophagy. 2010 Aug;6(6):754-63
references.pmid: 20574167
references.citation: Nat Immunol. 2011 Mar;12(3):222-30
references.pmid: 21151103
references.citation: Am J Pathol. 2010 May;176(5):2344-51
references.pmid: 20304961
references.citation: J Cell Biol. 2000 Nov 27;151(5):1025-34
references.pmid: 11086004
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Jun 15;304(12):L844-52
references.pmid: 23585228
references.citation: Autophagy. 2012 Apr;8(4):445-544
references.pmid: 22966490
references.citation: J Exp Med. 2006 Dec 25;203(13):2895-906
references.pmid: 17178917
references.citation: Am J Physiol Lung Cell Mol Physiol. 2014 Jan;306(2):L183-95
references.pmid: 24242010
references.citation: J Biol Chem. 2012 Jun 15;287(25):20922-30
references.pmid: 22547061
references.citation: Physiol Rev. 2004 Oct;84(4):1341-79
references.pmid: 15383654
references.citation: J Biol Chem. 1998 Aug 28;273(35):22267-71
references.pmid: 9712842
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18880-5
references.pmid: 20956295
references.citation: J Immunol. 2006 Oct 1;177(7):4853-60
references.pmid: 16982927
references.citation: Autophagy. 2013 Mar;9(3):374-85
references.pmid: 23322078
references.citation: J Cell Biol. 2009 May 4;185(3):381-5
references.pmid: 19398762
references.citation: Sci Signal. 2012 Feb 21;5(212):ra16
references.pmid: 22355189
references.citation: Cell Cycle. 2010 Sep 1;9(17):3515-33
references.pmid: 20855962
references.citation: Nat Cell Biol. 2007 Oct;9(10):1102-9
references.pmid: 17909521
references.citation: Cell Cycle. 2011 Jul 1;10(13):2140-50
references.pmid: 21670602
references.citation: J Mol Cell Biol. 2009 Oct;1(1):37-45
references.pmid: 19516051
references.citation: Nat Commun. 2013;4:2300
references.pmid: 23939249
references.citation: Free Radic Biol Med. 2011 May 15;50(10):1252-62
references.pmid: 21382479
references.citation: Mol Biol Cell. 2008 May;19(5):2092-100
references.pmid: 18321988
references.citation: Cardiovasc Res. 2008 Mar 1;77(4):791-9
references.pmid: 18065769
references.citation: J Exp Med. 2006 Oct 2;203(10):2377-89
references.pmid: 17000866
references.citation: Am J Respir Crit Care Med. 2011 Mar 1;183(5):649-58
references.pmid: 20889906
references.citation: Annu Rev Pathol. 2013 Jan 24;8:105-37
references.pmid: 23072311
references.citation: Autophagy. 2011 Apr;7(4):436-7
references.pmid: 21200154
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Jul 15;305(2):L93-107
references.pmid: 23709618