Protein kinase CK2-mediated phosphorylation of HDAC2 regulates co-repressor formation, deacetylase activity and acetylation of HDAC2 by cigarette smoke and aldehydes.
Histone deacetylase 2 (HDAC2) mediates the repression of pro-inflammatory genes by deacetylating core histones, RelA/p65 and the glucocorticoid receptor. Reduced level of HDAC2 is associated with steroid resistant inflammation caused by cigarette smoke (CS)-derived oxidants and aldehydes. However, the molecular mechanisms regulating HDAC2 in response to CS and aldehydes is not known. Here, we report that CS extract, and aldehyde acrolein induced phosphorylation of HDAC2 which was abolished by mutations at serine sites S(394), S(411), S(422) and S(424). HDAC2 phosphorylation required direct interaction with serine-phosphorylated protein kinase CK2alpha and involved reduced HDAC2 deacetylase activity. Furthermore, HDAC2 phosphorylation was required for HDAC2 interaction with transcription factors, co-repressor complex formation, CBP recruitment, acetylation on lysine residues and modulates transrepression activity. Thus, phospho-acetylation of HDAC2 negatively regulates its deacetylase activity which has implications in steroid resistance in chronic inflammatory conditions.
Adenuga
David
D
Department of Environmental Medicine, University of Rochester Medical Center, NY 14642, USA.
Rahman
Irfan
I
D000107:Acetylation; D000447:Aldehydes / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000378:metabolism; D047390:Casein Kinase II / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D002460:Cell Line; D045424:Complex Mixtures / Q000494:pharmacology; D020868:Gene Silencing; D056464:Histone Deacetylase 2 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport; D012097:Repressor Proteins / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D012906:Smoke; D014026:Nicotiana
D000447:Aldehydes; D045424:Complex Mixtures; D012097:Repressor Proteins; D012906:Smoke; D012694:Serine; D050882:CREB-Binding Protein; D047390:Casein Kinase II; D010744:Phosphoric Monoester Hydrolases; D056464:Histone Deacetylase 2
Science. 1998 Jan 30;279(5351):703-7
9445475
Respir Res. 2006 Oct 24;7:132
17062156
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8921-6
12070353
J Biol Chem. 2002 Sep 27;277(39):35783-6
12176973
J Exp Med. 2004 Sep 6;200(5):689-95
15337792
N Engl J Med. 2005 Oct 20;353(16):1711-23
16236742
FEBS Lett. 2001 May 4;496(1):44-8
11343704
Am J Respir Crit Care Med. 2009 Apr 1;179(7):542-8
19164702
J Biol Chem. 2002 May 31;277(22):19618-26
11919195
Curr Opin Pharmacol. 2004 Jun;4(3):257-62
15140417
Biochem J. 2007 May 15;404(1):15-21
17302559
J Cell Biol. 2005 Mar 14;168(6):887-97
15767461
Am J Respir Cell Mol Biol. 2008 Sep;39(3):312-23
18421014
Int J Cancer. 2008 Jan 15;122(2):333-41
17935135
Cell. 2009 Sep 4;138(5):1019-31
19698979
Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 1):1635-9
10556133
Biochem J. 2003 Mar 15;370(Pt 3):737-49
12429021
Lancet. 2009 May 30;373(9678):1905-17
19482216
EMBO J. 2004 Mar 10;23(5):1144-54
14976551
Am J Respir Cell Mol Biol. 2009 Apr;40(4):464-73
18927347
Biochem Biophys Res Commun. 2004 Feb 27;315(1):240-5
15013452
J Biol Chem. 2002 Aug 30;277(35):31826-33
12082111
Am J Physiol Lung Cell Mol Physiol. 2006 Jul;291(1):L46-57
16473865
Int J Biochem Cell Biol. 1997 Apr;29(4):551-4
9363631
J Biol Chem. 2001 Sep 14;276(37):35042-8
11470791
Oncogene. 2010 Jan 14;29(2):157-73
19855430
J Biol Chem. 2007 Nov 9;282(45):33227-36
17827154
J Biol Chem. 2002 Oct 4;277(40):37124-30
12145276
Annu Rev Physiol. 2009;71:451-64
18817512
Am J Med. 2002 Jul;113(1):59-65
12106623
Genes Dev. 1999 Oct 1;13(19):2490-501
10521394
Ann N Y Acad Sci. 1993 May 28;686:12-27; discussion 27-8
8512242
Mol Cell Biol. 1996 Mar;16(3):899-906
8622692
N Engl J Med. 2005 May 12;352(19):1967-76
15888697
Cell Mol Life Sci. 2009 Jun;66(11-12):1830-9
19387551
Eur Respir J. 1997 Dec;10(12):2754-60
9493656
J Biol Chem. 2009 Dec 11;284(50):34901-10
19822520
J Exp Med. 2006 Jan 23;203(1):7-13
16380507
Mol Cell. 2003 Oct;12(4):829-39
14580335
J Cell Biochem. 2004 Sep 1;93(1):57-67
15352162
Biochem Biophys Res Commun. 2009 Jul 3;384(3):366-71
19410558
Am J Respir Crit Care Med. 1997 Feb;155(2):542-8
9032192
J Cell Sci. 2002 Oct 15;115(Pt 20):3873-8
12244125
Mol Cell Biol. 2001 Oct;21(20):7065-77
11564889
Cell Signal. 2008 Nov;20(11):1942-51
18662771
Cell. 1997 May 2;89(3):341-7
9150133
J Biol Chem. 2000 Oct 20;275(42):32592-7
10938077
Am J Respir Crit Care Med. 2004 Jul 15;170(2):141-7
15087294
Mol Cell. 2006 Jun 9;22(5):669-79
16762839
Mol Biol Cell. 2008 Feb;19(2):655-67
18045992
Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12845-50
8917507
Eur Respir J. 2006 Jul;28(1):219-42
16816350
Nature. 1998 Feb 5;391(6667):597-601
9468139
Biochem J. 2003 Jan 1;369(Pt 1):1-15
12396231
J Biol Chem. 2001 Mar 2;276(9):6817-24
11102443
Trends Pharmacol Sci. 2009 Dec;30(12):647-55
19892411
Int J Oncol. 2006 Mar;28(3):685-93
16465374
Nature. 1998 Oct 29;395(6705):917-21
9804427
Am J Respir Crit Care Med. 2002 Jun 15;165(12):1592-6
12070058