title: Diametrically opposed effects of hypoxia and oxidative stress on two viral transactivators.
abstract: BACKGROUND
  Many pathogens exist in multiple physiological niches within the host. Differences between aerobic and anaerobic conditions are known to alter the expression of bacterial virulence factors, typically through the conditional activity of transactivators that modulate their expression. More recently, changes in physiological niches have been shown to affect the expression of viral genes. For many viruses, differences in oxygen tension between hypoxia and normoxia alter gene expression or function. Oxygen tension also affects many mammalian transactivators including AP-1, NFkB, and p53 by affecting the reduced state of critical cysteines in these proteins. We have recently determined that an essential cys-x-x-cys motif in the EBNA1 transactivator of Epstein-Barr virus is redox-regulated, such that transactivation is favoured under reducing conditions. The crucial Tat transactivator of human immunodeficiency virus (HIV) has an essential cysteine-rich region, and is also regulated by redox. Contrary to EBNA1, it is reported that Tat's activity is increased by oxidative stress. Here we have compared the effects of hypoxia, oxidative stress, and cellular redox modulators on EBNA1 and Tat.
  
  
  RESULTS
  Our results indicate that unlike EBNA1, Tat is less active during hypoxia. Agents that generate hydroxyl and superoxide radicals reduce EBNA1's activity but increase transactivation by Tat. The cellular redox modulator, APE1/Ref-1, increases EBNA1's activity, without any effect on Tat. Conversely, thioredoxin reductase 1 (TRR1) reduces Tat's function without any effect on EBNA1.
  
  
  CONCLUSIONS
  We conclude that oxygen partial pressure and oxidative stress affects the functions of EBNA1 and Tat in a dramatically opposed fashion. Tat is more active during oxidative stress, whereas EBNA1's activity is compromised under these conditions. The two proteins respond to differing cellular redox modulators, suggesting that the oxidized cysteine adduct is a disulfide bond(s) in Tat, but sulfenic acid in EBNA1. The effect of oxygen partial pressure on transactivator function suggests that changes in redox may underlie differences in virus-infected cells dependent upon the physiological niches they traffic to.
authors.affiliation: Department of Microbiology, Immunology and Parasitology, LSU Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Amber T
authors.initials: AT
authors.lastname: Washington
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Singh
authors.forename: Ashok
authors.initials: A
authors.lastname: Aiyar
mesh_terms: D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D006678:HIV / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D000860:Hypoxia; D018384:Oxidative Stress; D014764:Viral Proteins / Q000096:biosynthesis*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D019309:Epstein-Barr Virus Nuclear Antigens; D014764:Viral Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C417029:EBV-encoded nuclear antigen 1
references.citation: Science. 1988 Apr 1;240(4848):70-3
references.pmid: 2832944
references.citation: AIDS Res Hum Retroviruses. 1991 Jun;7(6):563-7
references.pmid: 1931232
references.citation: J Virol. 2009 May;83(9):4227-35
references.pmid: 19244333
references.citation: EMBO J. 1992 Sep;11(9):3323-35
references.pmid: 1380454
references.citation: AJNR Am J Neuroradiol. 2000 Jan;21(1):183-93
references.pmid: 10669248
references.citation: Nucleic Acids Res. 1989 May 11;17(9):3551-61
references.pmid: 2542902
references.citation: Nucleic Acids Res. 1990 Apr 11;18(7):1839-46
references.pmid: 2186367
references.citation: Mol Cell Biol. 1999 May;19(5):3349-59
references.pmid: 10207059
references.citation: Biochemistry. 2009 Jul 7;48(26):6213-23
references.pmid: 19366212
references.citation: J Neurovirol. 1998 Feb;4(1):90-4
references.pmid: 9531015
references.citation: J Biol Chem. 2008 Nov 28;283(48):33183-90
references.pmid: 18835810
references.citation: J Virol. 2004 Nov;78(21):11487-505
references.pmid: 15479791
references.citation: Chest. 1999 Jul;116(1 Suppl):101S
references.pmid: 10424622
references.citation: PLoS Pathog. 2009 Jun;5(6):e1000469
references.pmid: 19521517
references.citation: Virology. 2003 Jul 5;311(2):263-74
references.pmid: 12842617
references.citation: PLoS Pathog. 2007 Oct 19;3(10):1388-400
references.pmid: 17953479
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5111-6
references.pmid: 18364393
references.citation: Cell. 1981 Aug;25(2):385-98
references.pmid: 6269744
references.citation: Methods Enzymol. 1994;234:163-74
references.pmid: 7808290
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2005 Jul;141(3):225-40
references.pmid: 16039165
references.citation: J Virol. 1997 Jan;71(1):362-70
references.pmid: 8985358
references.citation: Free Radic Biol Med. 1996;21(5):641-9
references.pmid: 8891667
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4302-7
references.pmid: 15010533
references.citation: J Biol Chem. 1994 Mar 18;269(11):8366-75
references.pmid: 8132560
references.citation: J Biol Chem. 2006 Sep 22;281(38):27806-15
references.pmid: 16857675
references.citation: Magn Reson Med. 1994 Jul;32(1):88-97
references.pmid: 8084241
references.citation: Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7531-5
references.pmid: 1323841
references.citation: J Virol. 2003 Nov;77(21):11767-80
references.pmid: 14557661
references.citation: Gene. 2003 Nov 13;319:107-16
references.pmid: 14597176
references.citation: Cell. 1986 Mar 28;44(6):941-7
references.pmid: 2420471
references.citation: Proc Natl Acad Sci U S A. 1988 Sep;85(17):6297-300
references.pmid: 2842763
references.citation: J Cell Physiol. 2009 Nov;221(2):469-79
references.pmid: 19626680
references.citation: Gene. 1994 Aug 5;145(2):197-203
references.pmid: 8056331
references.citation: J Exp Med. 1999 Aug 16;190(4):567-76
references.pmid: 10449527
references.citation: Antioxid Redox Signal. 2009 Mar;11(3):621-38
references.pmid: 18715144
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6786-91
references.pmid: 9192643
references.citation: J Virol. 2007 Jun;81(12):6389-401
references.pmid: 17409162
references.citation: DNA Cell Biol. 1993 Apr;12(3):265-73
references.pmid: 8466649
references.citation: Adv Exp Med Biol. 1996;387:69-75
references.pmid: 8794196
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):239-44
references.pmid: 14688409
references.citation: J Biol Chem. 1995 Feb 3;270(5):2344-51
references.pmid: 7836468
references.citation: AIDS Res Hum Retroviruses. 1990 Nov;6(11):1257-63
references.pmid: 2078407
references.citation: Neurochem Res. 2004 Mar;29(3):561-7
references.pmid: 15038603
references.citation: J Biol Chem. 1998 Dec 4;273(49):33073-81
references.pmid: 9830062
references.citation: News Physiol Sci. 2000 Aug;15:202-208
references.pmid: 11390911
references.citation: Genes Dev. 1997 Mar 1;11(5):558-70
references.pmid: 9119221
references.citation: AIDS Res Hum Retroviruses. 1993 Apr;9(4):299-306
references.pmid: 8512745
references.citation: J Biol Chem. 1991 Jun 5;266(16):10505-9
references.pmid: 1709934
references.citation: Eur J Immunol. 2000 Apr;30(4):1120-6
references.pmid: 10760801
references.citation: J Biol Chem. 1991 Jun 25;266(18):11421-4
references.pmid: 1904863
references.citation: Int J Immunopharmacol. 1996 Oct;18(10):545-52
references.pmid: 9080248
references.citation: Antioxid Redox Signal. 2002 Jun;4(3):471-7
references.pmid: 12215214
references.citation: EMBO J. 1997 May 15;16(10):2590-8
references.pmid: 9184206
references.citation: Am J Physiol. 1999 Mar;276(3):L530-9
references.pmid: 10070119
references.citation: J Clin Virol. 2007 May;39(1):9-15
references.pmid: 17368087
references.citation: Science. 1985 Jul 5;229(4708):74-7
references.pmid: 2990041