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Autophagy and apoptosis play critical roles in cellular homeostasis and survival. Subtilase cytotoxin (SubAB), produced by non-O157 type Shiga-toxigenic Escherichia coli (STEC), is an important virulence factor in disease. SubAB, a protease, cleaves a specific site on the endoplasmic reticulum (ER) chaperone protein BiP/GRP78, leading to ER stress, and induces apoptosis. Here we report that in HeLa cells, activation of a PERK (RNA-dependent protein kinase [PKR]-like ER kinase)-eIF2α (α subunit of eukaryotic initiation factor 2)-dependent pathway by SubAB-mediated BiP cleavage negatively regulates autophagy and induces apoptosis through death-associated protein 1 (DAP1). We found that SubAB treatment decreased the amounts of autophagy markers LC3-II and p62 as well as those of mTOR (mammalian target of rapamycin) signaling proteins ULK1 and S6K. These proteins showed increased expression levels in PERK knockdown or DAP1 knockdown cells. In addition, depletion of DAP1 in HeLa cells dramatically inhibited the SubAB-stimulated apoptotic pathway: SubAB-induced Bax/Bak conformational changes, Bax/Bak oligomerization, cytochrome c release, activation of caspases, and poly(ADP-ribose) polymerase (PARP) cleavage. These results show that DAP1 is a key regulator, through PERK-eIF2α-dependent pathways, of the induction of apoptosis and reduction of autophagy by SubAB.

Titel:	DAP1, a negative regulator of autophagy, controls SubAB-mediated apoptosis and autophagy.
Autor/in / Beteiligte Person:	Yahiro, K ; Tsutsuki, H ; Ogura, K ; Nagasawa, S ; Moss, J ; Noda, M
Link:	Full Text Finder (Volltext)
Zeitschrift:	Infection and immunity, Jg. 82 (2014-11-01), Heft 11, S. 4899-908
Veröffentlichung:	Washington, DC : American Society For Microbiology ; <i>Original Publication</i>: [Bethesda, Md.] American Society for Microbiology., 2014
Medientyp:	academicJournal
ISSN:	1098-5522 (electronic)
DOI:	10.1128/IAI.02213-14
Schlagwort:	Apoptosis Regulatory Proteins genetics Endoplasmic Reticulum Chaperone BiP Escherichia coli Escherichia coli Proteins genetics HeLa Cells Humans Subtilisins genetics bcl-2 Homologous Antagonist-Killer Protein genetics bcl-2 Homologous Antagonist-Killer Protein metabolism bcl-2-Associated X Protein genetics bcl-2-Associated X Protein metabolism Apoptosis physiology Apoptosis Regulatory Proteins metabolism Autophagy physiology Escherichia coli Proteins metabolism Gene Expression Regulation immunology Subtilisins metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Language: English [Infect Immun] 2014 Nov; Vol. 82 (11), pp. 4899-908. <i>Date of Electronic Publication: </i>2014 Sep 02. MeSH Terms: Apoptosis / physiology ; Apoptosis Regulatory Proteins / metabolism ; Autophagy / physiology ; Escherichia coli Proteins / metabolism ; Gene Expression Regulation / immunology ; Subtilisins / metabolism ; Apoptosis Regulatory Proteins / genetics ; Endoplasmic Reticulum Chaperone BiP ; Escherichia coli ; Escherichia coli Proteins / genetics ; HeLa Cells ; Humans ; Subtilisins / genetics ; bcl-2 Homologous Antagonist-Killer Protein / genetics ; bcl-2 Homologous Antagonist-Killer Protein / metabolism ; bcl-2-Associated X Protein / genetics ; bcl-2-Associated X Protein / metabolism References: J Immunol. 2009 Jul 15;183(2):1480-7. (PMID: 19561103) ; J Cell Sci. 2009 Jun 1;122(Pt 11):1707-11. (PMID: 19461070) ; Annu Rev Physiol. 2013;75:241-62. (PMID: 23216414) ; Traffic. 2009 Oct;10(10):1502-17. (PMID: 19678899) ; J Infect Dis. 2004 Feb 1;189(3):355-9. (PMID: 14745691) ; Cell Death Dis. 2010;1:e18. (PMID: 21364619) ; J Biol Chem. 2003 Feb 14;278(7):5367-76. (PMID: 12454021) ; Exp Mol Med. 2012 Feb 29;44(2):99-108. (PMID: 22257885) ; Infect Immun. 2010 Nov;78(11):4691-6. (PMID: 20713620) ; Pharmacol Res. 2012 Dec;66(6):513-25. (PMID: 22982482) ; Genes Dev. 1995 Jan 1;9(1):15-30. (PMID: 7828849) ; J Clin Invest. 2012 Dec;122(12):4621-34. (PMID: 23143306) ; Hum Mol Genet. 2006 Apr 1;15(7):1209-16. (PMID: 16497721) ; Infect Immun. 2007 Jan;75(1):488-96. (PMID: 17101670) ; Enferm Infecc Microbiol Clin. 2007 Nov;25(9):603-4. (PMID: 17953903) ; Annu Rev Cell Dev Biol. 2011;27:107-32. (PMID: 21801009) ; J Vet Med Sci. 2010 May;72(5):589-97. (PMID: 20103992) ; Cell Microbiol. 2008 Apr;10(4):921-9. (PMID: 18005237) ; Curr Biol. 2010 Jun 22;20(12):1093-8. (PMID: 20537536) ; Autophagy. 2009 Apr;5(3):370-9. (PMID: 19164948) ; Cell Microbiol. 2008 Mar;10(3):795-806. (PMID: 18042253) ; Autophagy. 2008 Oct;4(7):849-50. (PMID: 18758232) ; Infect Immun. 2012 Nov;80(11):3939-51. (PMID: 22949549) ; J Exp Med. 2004 Jul 5;200(1):35-46. (PMID: 15226357) ; Infect Immun. 2012 May;80(5):1803-14. (PMID: 22354021) ; Oncogene. 2009 Jan 22;28(3):334-44. (PMID: 18931699) ; Oncol Rep. 2014 Jan;31(1):175-82. (PMID: 24270644) ; Autophagy. 2011 Sep;7(9):957-65. (PMID: 21606683) ; J Clin Microbiol. 2005 Jun;43(6):2944-7. (PMID: 15956427) ; N Engl J Med. 1983 Mar 24;308(12):681-5. (PMID: 6338386) ; J Cell Biochem. 2009 Aug 1;107(5):973-83. (PMID: 19492336) ; Cell Death Differ. 2011 Apr;18(4):571-80. (PMID: 21311563) ; Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1829-34. (PMID: 17267617) ; Cell Microbiol. 2011 Oct;13(10):1479-96. (PMID: 21722286) ; Eur J Clin Microbiol Infect Dis. 2010 Nov;29(11):1395-9. (PMID: 20680367) ; Cell Microbiol. 2011 Jul;13(7):992-1013. (PMID: 21501364) ; Autophagy. 2010 Nov;6(8):1179-80. (PMID: 20818178) ; J Biol Chem. 2007 Aug 17;282(33):24131-45. (PMID: 17580304) ; Autophagy. 2008 Oct;4(7):887-95. (PMID: 18769149) ; Autophagy. 2007 Nov-Dec;3(6):542-5. (PMID: 17611390) ; Microb Pathog. 2010 Oct;49(4):153-63. (PMID: 20561923) ; Nature. 2006 Oct 5;443(7111):548-52. (PMID: 17024087) ; Nihon Rinsho. 1997 Mar;55(3):686-92. (PMID: 9086782) ; Infect Immun. 2014 Sep;82(9):3542-54. (PMID: 24914224) ; Mol Biol Cell. 2009 Apr;20(7):1992-2003. (PMID: 19225151) ; J Clin Microbiol. 2009 Sep;47(9):3058-9. (PMID: 19571032) ; Cell Death Differ. 2010 Dec;17(12):1807-15. (PMID: 20865012) ; J Biol Chem. 1999 Apr 9;274(15):10145-53. (PMID: 10187798) ; Nat Med. 2010 Jan;16(1):90-7. (PMID: 19966812) ; Nature. 2008 Dec 4;456(7222):648-52. (PMID: 18971931) ; J Am Soc Nephrol. 2010 Oct;21(10):1702-12. (PMID: 20705711) ; Oncogene. 2013 Oct 10;32(41):4932-40. (PMID: 23160380) ; FEMS Microbiol Lett. 2007 Sep;274(2):329-34. (PMID: 17651390) ; Oncogene. 1998 Dec 24;17(25):3331-40. (PMID: 9916995) ; J Clin Microbiol. 2010 Jan;48(1):178-83. (PMID: 19940059) ; Cancer Genomics Proteomics. 2012 Jul-Aug;9(4):199-201. (PMID: 22798505) ; Infect Immun. 2009 Jul;77(7):2919-24. (PMID: 19380466) ; Infect Immun. 2011 Feb;79(2):617-27. (PMID: 21098100) ; J Biol Chem. 2010 Nov 5;285(45):34447-59. (PMID: 20805228) ; J Biol Chem. 1995 Jan 13;270(2):815-22. (PMID: 7822316) Grant Information: United States Intramural NIH HHS Substance Nomenclature: 0 (Apoptosis Regulatory Proteins) ; 0 (BAK1 protein, human) ; 0 (BAX protein, human) ; 0 (DAP protein, human) ; 0 (Endoplasmic Reticulum Chaperone BiP) ; 0 (Escherichia coli Proteins) ; 0 (HSPA5 protein, human) ; 0 (bcl-2 Homologous Antagonist-Killer Protein) ; 0 (bcl-2-Associated X Protein) ; EC 3.4.21.- (Subtilisins) ; EC 3.4.21.- (subtilase cytotoxin, E coli) Entry Date(s): Date Created: 20140904 Date Completed: 20141215 Latest Revision: 20211203 Update Code: 20240513 PubMed Central ID: PMC4249318

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DAP1, a negative regulator of autophagy, controls SubAB-mediated apoptosis and autophagy.