Redox signaling, alkylation (carbonylation) of conserved cysteines inactivates class I histone deacetylases 1, 2, and 3 and antagonizes their transcriptional repressor function.
Cells use redox signaling to adapt to oxidative stress. For instance, certain transcription factors exist in a latent state that may be disrupted by oxidative modifications that activate their transcription potential. We hypothesized that DNA-binding sites (response elements) for redox-sensitive transcription factors may also exist in a latent state, maintained by co-repressor complexes containing class I histone deacetylase (HDAC) enzymes, and that HDAC inactivation by oxidative stress may antagonize deacetylase activity and unmask electrophile-response elements, thus activating transcription. Electrophiles suitable to test this hypothesis include reactive carbonyl species, often derived from peroxidation of arachidonic acid. We report that alpha,beta-unsaturated carbonyl compounds, e.g. the cyclopentenone prostaglandin, 15-deoxy-Delta12,14-PGJ(2) (15d-PGJ(2)), and 4-hydroxy-2-nonenal (4HNE), alkylate (carbonylate), a subset of class I HDACs including HDAC1, -2, and -3, but not HDAC8. Covalent modification at two conserved cysteine residues, corresponding to Cys(261) and Cys(273) in HDAC1, coincided with attenuation of histone deacetylase activity, changes in histone H3 and H4 acetylation patterns, derepression of a LEF1.beta-catenin model system, and transcription of HDAC-repressed genes, e.g. heme oxygenase-1 (HO-1), Gadd45, and HSP70. Identification of particular class I HDACs as components of the redox/electrophile-responsive proteome offers a basis for understanding how cells stratify their responses to varying degrees of pathophysiological oxidative stress associated with inflammation, cancer, and metabolic syndrome.
Doyle
Kelly
K
Department of Medicinal Chemistry, University of Utah School of Pharmacy, Salt Lake City, Utah 84112, USA.
Fitzpatrick
F A
FA
D002460:Cell Line; D003545:Cysteine / Q000737:chemistry*; D006570:Heterochromatin / Q000737:chemistry; D056284:Histone Deacetylase 1 / Q000737:chemistry; D056464:Histone Deacetylase 2 / Q000737:chemistry; D006655:Histone Deacetylases / Q000737:chemistry*; D006801:Humans; D007120:Immunochemistry / Q000379:methods; D007249:Inflammation; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011453:Prostaglandins / Q000737:chemistry; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
D003545:Cysteine; D006570:Heterochromatin; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D011453:Prostaglandins; D000099186:Histone Deacetylase 3
Antioxid Redox Signal. 2010 Mar;12(3):393-404
19686045
Science. 1996 Apr 19;272(5260):408-11
8602529
J Biol Chem. 2002 Mar 22;277(12):10459-66
11786541
J Clin Invest. 1997 Feb 1;99(3):424-32
9022075
Protein Sci. 2008 Feb;17(2):299-312
18227433
J Biol Chem. 2007 Nov 9;282(45):32623-9
17855346
Genes Dev. 1998 Mar 1;12(5):599-606
9499396
Mutat Res. 1990 May;238(3):223-33
2342513
Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20979-84
18077391
Genes Dev. 2001 Nov 1;15(21):2786-96
11691830
Circ Res. 2008 Feb 15;102(3):273-4
18276922
Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14503-8
8962081
Biochem J. 2004 Mar 1;378(Pt 2):373-82
14616092
Am J Respir Crit Care Med. 2002 Aug 15;166(4):490-5
12186826
Nature. 2002 Dec 19-26;420(6917):846-52
12490957
J Biol Chem. 2001 May 25;276(21):18223-8
11359792
Cell. 1999 Nov 24;99(5):447-50
10589671
Nat Med. 1999 Jun;5(6):698-701
10371510
Chem Res Toxicol. 2006 Feb;19(2):173-94
16485894
Nature. 2008 Jul 24;454(7203):428-35
18650913
J Cell Physiol. 2009 Jun;219(3):677-87
19202556
J Biol Chem. 2006 Feb 3;281(5):2598-604
16311241
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7367-72
12032289
J Biol Chem. 2002 Jul 5;277(27):24368-75
12006588
J Biol Chem. 2003 Jan 10;278(2):745-50
12424231
J Biol Chem. 1999 Apr 16;274(16):10863-8
10196163
Nat Immunol. 2005 Dec;6(12):1191-7
16369558
Biochem J. 2008 Apr 15;411(2):297-306
18237271
J Biol Chem. 1983 Oct 10;258(19):11713-8
6578214
J Biol Chem. 2008 Aug 8;283(32):21837-41
18445586
Methods. 2003 Sep;31(1):12-23
12893169
Curr Opin Cell Biol. 2001 Jun;13(3):263-73
11343896
Ann N Y Acad Sci. 2006 Dec;1091:548-70
17341644
Cell. 2004 Mar 19;116(6):883-95
15035989
Chem Res Toxicol. 2008 Jan;21(1):138-44
18052108
J Cell Sci. 2002 Feb 15;115(Pt 4):689-98
11865025
J Biol Chem. 2001 Sep 21;276(38):35530-6
11466314
Mol Cell Biol. 2000 Sep;20(18):6882-90
10958684
Trends Mol Med. 2003 Apr;9(4):169-76
12727143
Nature. 2000 Jan 6;403(6765):103-8
10638762
Nature. 2003 Jun 12;423(6941):769-73
12802338
J Pharmacol Exp Ther. 1986 Nov;239(2):500-5
3772804
J Biol Chem. 2008 Jun 6;283(23):15539-43
18285327
Trends Immunol. 2001 Apr;22(4):199-204
11274925
Nature. 2008 Sep 18;455(7211):411-5
18754010
J Med Chem. 2005 Nov 3;48(22):6936-47
16250652
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19183-7
19047631
Cell. 1997 May 2;89(3):341-7
9150133
Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4844-9
10781090
Nat Rev Immunol. 2008 May;8(5):349-61
18437155
Mol Cell Proteomics. 2009 Apr;8(4):670-80
19054759
Antioxid Redox Signal. 2005 Jan-Feb;7(1-2):25-31
15650393
Bioorg Med Chem. 2009 Mar 15;17(6):2189-98
19022675
Circ Res. 2008 Feb 15;102(3):310-8
18079412
J Pharmacol Exp Ther. 1986 Nov;239(2):506-11
3772805
Free Radic Biol Med. 1991;11(1):81-128
1937131
FEBS Lett. 2005 Oct 24;579(25):5803-8
16223487
J Pharmacol Exp Ther. 1987 Jul;242(1):306-11
3302206
Curr Opin Chem Biol. 1997 Oct;1(3):300-8
9667866
J Biol Chem. 1998 Jun 26;273(26):16058-66
9632657
Nat Protoc. 2007;2(6):1445-57
17545981
Prostaglandins. 1985 Sep;30(3):383-400
3864190
Science. 1993 Jan 1;259(5091):44-5
8418493
Annu Rev Pharmacol Toxicol. 2004;44:325-47
14744249