title: DRAM triggers lysosomal membrane permeabilization and cell death in CD4(+) T cells infected with HIV.
abstract: Productive HIV infection of CD4(+) T cells leads to a caspase-independent cell death pathway associated with lysosomal membrane permeabilization (LMP) and cathepsin release, resulting in mitochondrial outer membrane permeabilization (MOMP). Herein, we demonstrate that HIV infection induces damage-regulated autophagy modulator (DRAM) expression in a p53-dependent manner. Knocking down the expression of DRAM and p53 genes with specific siRNAs inhibited autophagy and LMP. However, inhibition of Atg5 and Beclin genes that prevents autophagy had a minor effect on LMP and cell death. The knock down of DRAM gene inhibited cytochrome C release, MOMP and cell death. However, knocking down DRAM, we increased viral infection and production. Our study shows for the first time the involvement of DRAM in host-pathogen interactions, which may represent a mechanism of defense via the elimination of infected cells.
authors: CNRS FRE 3235, Université Paris Descartes, Paris, France.
authors: Mireille
authors: M
authors: Laforge
authors: Sophie
authors: S
authors: Limou
authors: Francis
authors: F
authors: Harper
authors: Nicoletta
authors: N
authors: Casartelli
authors: Vasco
authors: V
authors: Rodrigues
authors: Ricardo
authors: R
authors: Silvestre
authors: Houda
authors: H
authors: Haloui
authors: Jean-Francois
authors: JF
authors: Zagury
authors: Anna
authors: A
authors: Senik
authors: Jerome
authors: J
authors: Estaquier
mesh_terms: D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006678:HIV / Q000502:physiology*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010539:Permeability; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C512709:DRAM1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c
references: J Virol. 2007 Oct;81(20):11426-40
references: 17670831
references: J Biol Chem. 2001 Feb 2;276(5):3149-57
references: 11073962
references: Autophagy. 2008 Nov;4(8):1054-6
references: 18776740
references: Science. 2008 Feb 15;319(5865):921-6
references: 18187620
references: J Virol. 2002 Mar;76(6):2692-702
references: 11861836
references: AIDS. 2003 Jul 25;17(11):1585-96
references: 12853740
references: AIDS Res Hum Retroviruses. 2004 Nov;20(11):1230-43
references: 15588345
references: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6286-91
references: 11959917
references: J Exp Med. 1995 Dec 1;182(6):1759-67
references: 7500020
references: J Cell Biol. 2009 Jul 27;186(2):255-68
references: 19635843
references: J Biophys Biochem Cytol. 1961 Feb;9:409-14
references: 13764136
references: J Exp Med. 1998 Apr 6;187(7):1113-22
references: 9529327
references: J Exp Med. 1994 Jan 1;179(1):115-23
references: 7903679
references: Cancer Res. 2008 Aug 15;68(16):6623-33
references: 18701486
references: Nat Cell Biol. 2004 Dec;6(12):1221-8
references: 15558033
references: Cancer Res. 2007 Dec 1;67(23):11176-85
references: 18056442
references: Nature. 2003 Jul 31;424(6948):516-23
references: 12872134
references: Virology. 2009 Oct 10;393(1):160-7
references: 19692106
references: J Immunol. 2008 Dec 15;181(12):8460-77
references: 19050264
references: PLoS Pathog. 2006 Dec;2(12):e127
references: 17140287
references: EMBO J. 2007 Jan 24;26(2):313-24
references: 17245426
references: Nature. 2004 Dec 23;432(7020):1032-6
references: 15525940
references: Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14079-84
references: 15371598
references: J Exp Med. 1965 Mar 1;121:463-76
references: 14270244
references: Science. 2000 Dec 1;290(5497):1717-21
references: 11099404
references: Cell. 2007 Dec 14;131(6):1149-63
references: 18083104
references: AIDS. 2005 Apr 29;19(7):663-73
references: 15821392
references: FASEB J. 2001 Jan;15(1):5-6
references: 11099484
references: J Exp Med. 2001 Oct 15;194(8):1097-110
references: 11602639
references: J Virol. 2001 Apr;75(8):3916-24
references: 11264380
references: J Virol. 1998 Oct;72(10):8061-72
references: 9733846
references: Cell Death Differ. 2007 Oct;14(10):1747-58
references: 17612589
references: Oncogene. 2004 Apr 12;23(16):2746-56
references: 15077138
references: PLoS One. 2010 Jul 22;5(7):e11733
references: 20661303
references: Autophagy. 2008 Feb;4(2):151-75
references: 18188003
references: Nature. 2005 Apr 28;434(7037):1093-7
references: 15793563
references: Cell Death Differ. 2009 Jan;16(1):12-20
references: 18600232
references: Nature. 2007 Dec 20;450(7173):1253-7
references: 18097414
references: Science. 2004 Nov 5;306(5698):990-5
references: 15528435
references: Retrovirology. 2009 Jan 15;6:5
references: 19146679
references: Immunity. 2010 May 28;32(5):654-69
references: 20451412
references: Genome Res. 2001 Jul;11(7):1198-204
references: 11435401
references: Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):873-8
references: 9023349
references: Cell. 2005 Jan 28;120(2):159-62
references: 15680321
references: J Clin Invest. 2006 Aug;116(8):2161-72
references: 16886061
references: J Virol. 2002 May;76(10):5082-93
references: 11967324
references: Oncogene. 2004 Apr 12;23(16):2881-90
references: 15077151
references: Nature. 2010 Jun 17;465(7300):942-6
references: 20526321
references: J Natl Cancer Inst. 1967 Oct;39(4):775-780, 782-7
references: 18623936
references: AIDS. 2008 Mar 30;22(6):695-9
references: 18356598
references: J Biol Chem. 2003 Aug 15;278(33):31401-11
references: 12782632
references: Cell. 1991 May 17;65(4):651-62
references: 2032289
references: Nature. 1968 Jun 15;218(5146):1063-4
references: 4297810
references: J Immunol. 2006 Nov 15;177(10):6685-94
references: 17082581
references: J Virol. 2002 May;76(10):5094-107
references: 11967325
references: J Biol Chem. 2002 Jan 11;277(2):1477-87
references: 11689551
references: J Virol. 1970 Feb;5(2):226-9
references: 4194168
references: Nat Rev Immunol. 2007 Oct;7(10):767-77
references: 17767194
references: Cell. 2006 Jul 14;126(1):121-34
references: 16839881
references: Autophagy. 2011 Mar;7(3):279-96
references: 21189453
references: Cell Host Microbe. 2010 Feb 18;7(2):115-27
references: 20159618
references: Cell Cycle. 2005 Mar;4(3):449-52
references: 15738654
references: Nature. 2005 Apr 28;434(7037):1148-52
references: 15793562
references: Cell Death Differ. 2005 Aug;12 Suppl 1:979-90
references: 15818408
references: Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9431-5
references: 7937784
references: J Biol Chem. 2003 Jul 11;278(28):25879-86
references: 12738771