title: p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene.
abstract: p73, a member of the p53 tumor suppressor family, is involved in neurogenesis, sensory pathways, immunity, inflammation, and tumorigenesis. How p73 is able to participate in such a broad spectrum of different biological processes is still largely unknown. Here, we report a novel role of p73 in regulating lipid metabolism by direct transactivation of the promoter of autophagy-related protein 5 (ATG5), a gene whose product is required for autophagosome formation. Following nutrient deprivation, the livers of p73-deficient mice demonstrate a massive accumulation of lipid droplets, together with a low level of autophagy, suggesting that triglyceride hydrolysis into fatty acids is blocked owing to deficient autophagy (macrolipophagy). Compared with wild-type mice, mice functionally deficient in all the p73 isoforms exhibit decreased ATG5 expression and lower levels of autophagy in multiple organs. We further show that the TAp73α is the critical p73 isoform responsible for inducing ATG5 expression in a p53-independent manner and demonstrate that ATG5 gene transfer can correct autophagy and macrolipophagy defects in p73-deficient hepatocytes. These data strongly suggest that the p73-ATG5 axis represents a novel, key pathway for regulating lipid metabolism through autophagy. The identification of p73 as a major regulator of autophagy suggests that it may have an important role in preventing or delaying disease and aging by maintaining a homeostatic control.
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Z
authors.initials: Z
authors.lastname: He
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Agostini
authors.forename: S
authors.initials: S
authors.lastname: Yousefi
authors.forename: A
authors.initials: A
authors.lastname: Perren
authors.forename: M P
authors.initials: MP
authors.lastname: Tschan
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.forename: H U
authors.initials: HU
authors.lastname: Simon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D000071187:Autophagy-Related Protein 5; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C502778:ATG5 protein, human; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
references.citation: Cell. 2011 Sep 2;146(5):682-95
references.pmid: 21884931
references.citation: Gastroenterology. 2011 May;140(6):1738-47
references.pmid: 21530740
references.citation: J Exp Med. 1998 Nov 2;188(9):1763-8
references.pmid: 9802988
references.citation: Cell Death Dis. 2012 Oct 11;3:e400
references.pmid: 23059819
references.citation: Science. 2011 Aug 26;333(6046):1109-12
references.pmid: 21868666
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 20;106(3):797-802
references.pmid: 19139399
references.citation: Trends Cell Biol. 2008 May;18(5):244-52
references.pmid: 18406616
references.citation: Lipids. 2009 Jun;44(6):511-9
references.pmid: 19373502
references.citation: Cell Death Differ. 2010 Dec;17(12):1816-29
references.pmid: 21076477
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21093-8
references.pmid: 22160687
references.citation: Mol Cell Biol. 2004 Dec;24(24):10593-610
references.pmid: 15572666
references.citation: Mol Cell. 2010 Oct 22;40(2):280-93
references.pmid: 20965422
references.citation: Nat Rev Mol Cell Biol. 2011 Apr;12(4):259-65
references.pmid: 21427767
references.citation: Cell Death Dis. 2012 Sep 06;3:e387
references.pmid: 22951984
references.citation: J Lipid Res. 1984 Dec 1;25(12):1358-67
references.pmid: 6397548
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21099-104
references.pmid: 22160706
references.citation: Nature. 2013 Feb 21;494(7437):323-7
references.pmid: 23389440
references.citation: Cell Death Dis. 2012 Oct 04;3:e397
references.pmid: 23034332
references.citation: Cell Death Differ. 2012 Jan;19(1):107-20
references.pmid: 21760595
references.citation: Cell. 2011 Nov 11;147(4):728-41
references.pmid: 22078875
references.citation: Nature. 2000 Mar 2;404(6773):99-103
references.pmid: 10716451
references.citation: Nature. 2008 Sep 18;455(7211):396-400
references.pmid: 18701890
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17609-10
references.pmid: 19826090
references.citation: J Lipid Res. 2007 Nov;48(11):2334-43
references.pmid: 17720960
references.citation: Nat Cell Biol. 2010 Sep;12(9):823-30
references.pmid: 20811354
references.citation: Nature. 2009 Apr 30;458(7242):1131-5
references.pmid: 19339967
references.citation: Semin Immunopathol. 2010 Dec;32(4):373-81
references.pmid: 20857294
references.citation: Oncogene. 2007 Apr 2;26(15):2220-5
references.pmid: 17401431
references.citation: J Biol Chem. 2006 Dec 29;281(52):40236-41
references.pmid: 17074755
references.citation: Nat Cell Biol. 2006 Oct;8(10):1124-32
references.pmid: 16998475
references.citation: Cell Death Dis. 2012 Jun 07;3:e318
references.pmid: 22673192
references.citation: J Cell Biol. 2005 Nov 21;171(4):603-14
references.pmid: 16286508
references.citation: EMBO J. 2010 Jun 2;29(11):1792-802
references.pmid: 20418806
references.citation: Cell Death Differ. 2004 Oct;11(10):1150-2
references.pmid: 15243585
references.citation: Cell Metab. 2007 Dec;6(6):458-71
references.pmid: 18054315
references.citation: Cell Death Differ. 2013 Apr;20(4):611-9
references.pmid: 23238567
references.citation: Nat Cell Biol. 2008 Jun;10(6):676-87
references.pmid: 18454141
references.citation: Genes Dev. 2012 Sep 15;26(18):2009-14
references.pmid: 22987635
references.citation: Cell Death Differ. 2007 Jun;14(6):1071-9
references.pmid: 17304243
references.citation: J Cell Sci. 2001 Oct;114(Pt 20):3619-29
references.pmid: 11707514
references.citation: Immunol Rev. 2011 Mar;240(1):92-104
references.pmid: 21349088
references.citation: Genes Dev. 2008 Oct 1;22(19):2677-91
references.pmid: 18805989
references.citation: Cell Death Dis. 2012 May 03;3:e303
references.pmid: 22552280
references.citation: J Histochem Cytochem. 1988 Dec;36(12):1471-4
references.pmid: 2461410
references.citation: Cell Death Differ. 2011 Dec;18(12):1815-24
references.pmid: 21941372
references.citation: Science. 2011 Jun 17;332(6036):1429-33
references.pmid: 21617040
references.citation: Autophagy. 2009 Jan;5(1):114-6
references.pmid: 19001857
references.citation: Cell. 2006 Jul 14;126(1):121-34
references.pmid: 16839881
references.citation: Cell Death Differ. 2012 May;19(5):816-26
references.pmid: 22075982
references.citation: Am J Pathol. 1979 Jun;95(3):633-41
references.pmid: 88183
references.citation: J Cell Biol. 2001 Feb 19;152(4):657-68
references.pmid: 11266458
references.citation: Science. 2004 Nov 19;306(5700):1383-6
references.pmid: 15550674
references.citation: Autophagy. 2008 May;4(4):457-66
references.pmid: 18253089