title: Multi-omic data integration links deleted in breast cancer 1 (DBC1) degradation to chromatin remodeling in inflammatory response.
abstract: This study investigated the dynamics of ubiquitinated proteins after the inflammatory stimulation of RAW 264.7 macrophage-like cells with bacterial lipopolysaccharide. Ubiquitination is a common protein post-translational modification that regulates many key cellular functions. We demonstrated that levels of global ubiquitination and K48 and K63 polyubiquitin chains change after lipopolysaccharide stimulation. Quantitative proteomic analysis identified 1199 ubiquitinated proteins, 78 of which exhibited significant changes in ubiquitination levels following stimulation. Integrating the ubiquitinome data with global proteomic and transcriptomic results allowed us to identify a subset of 88 proteins that were targeted for degradation after lipopolysaccharide stimulation. Using cellular assays and Western blot analyses, we biochemically validated DBC1 (a histone deacetylase inhibitor) as a degradation substrate that is targeted via an orchestrated mechanism utilizing caspases and the proteasome. The degradation of DBC1 releases histone deacetylase activity, linking lipopolysaccharide activation to chromatin remodeling in caspase- and proteasome-mediated signaling.
authors: Biological Science Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.
authors: Ernesto S
authors: ES
authors: Nakayasu
authors: Roslyn N
authors: RN
authors: Brown
authors: Charles
authors: C
authors: Ansong
authors: Michael A
authors: MA
authors: Sydor
authors: Sayed
authors: S
authors: Imtiaz
authors: Cosmin
authors: C
authors: Mihai
authors: Ryan
authors: R
authors: Sontag
authors: Kim K
authors: KK
authors: Hixson
authors: Matthew E
authors: ME
authors: Monroe
authors: Tiago J P
authors: TJ
authors: Sobreira
authors: Galya
authors: G
authors: Orr
authors: Vladislav A
authors: VA
authors: Petyuk
authors: Feng
authors: F
authors: Yang
authors: Richard D
authors: RD
authors: Smith
authors: Joshua N
authors: JN
authors: Adkins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D020543:Proteome; D059467:Transcriptome; D057149:Ubiquitinated Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D002843:Chromatin; D008070:Lipopolysaccharides; D020543:Proteome; D057149:Ubiquitinated Proteins
references: FASEB J. 2006 Jul;20(9):1315-27
references: 16816106
references: Proteomics. 2011 May;11(10):2019-26
references: 21500348
references: Curr Opin Microbiol. 2010 Feb;13(1):41-6
references: 20036613
references: Oncogene. 2005 Jul 21;24(31):4908-20
references: 15824730
references: J Infect Dis. 2011 Nov;204(9):1367-74
references: 21921209
references: Biochim Biophys Acta. 2000 Dec 15;1524(2-3):178-82
references: 11113565
references: J Clin Invest. 2010 Feb;120(2):545-58
references: 20071779
references: Nat Clin Pract Rheumatol. 2008 Jan;4(1):34-42
references: 18172447
references: Mol Cell. 2008 Jan 18;29(1):69-80
references: 18206970
references: Nat Protoc. 2007;2(6):1445-57
references: 17545981
references: Nat Rev Immunol. 2011 Dec 09;12(1):35-48
references: 22158412
references: Nature. 2007 Jun 21;447(7147):972-8
references: 17538624
references: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8662-7
references: 11447297
references: J Immunol. 2008 Apr 1;180(7):5045-56
references: 18354230
references: Mol Cell Biol. 2005 May;25(10):3886-95
references: 15870263
references: Nat Cell Biol. 2008 May;10(5):602-10
references: 18391941
references: J Biol Chem. 2010 Dec 24;285(52):40830-7
references: 21030595
references: J Biol Chem. 2012 Mar 30;287(14):11002-10
references: 22262844
references: Nature. 2012 Mar 25;484(7394):386-9
references: 22446626
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: Nat Struct Mol Biol. 2011 May;18(5):520-8
references: 21540891
references: J Proteome Res. 2008 Aug;7(8):3354-63
references: 18597511
references: Anal Chem. 2008 Jan 1;80(1):294-302
references: 18044960
references: Immunol Res. 2005;31(3):243-60
references: 15888915
references: Immunobiology. 2005;210(2-4):97-107
references: 16164016
references: J Leukoc Biol. 2010 Jun;87(6):1103-14
references: 20200406
references: Nature. 2008 Jan 31;451(7178):587-90
references: 18235502
references: Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):745-50
references: 11805328
references: J Biol Chem. 2011 Jul 1;286(26):23319-33
references: 21460227
references: J Struct Biol. 2002 Oct-Dec;140(1-3):189-99
references: 12490167
references: Mol Syst Biol. 2012 Jun 26;8:558
references: 22735334
references: Immunol Rev. 2012 Mar;246(1):107-24
references: 22435550
references: Nat Immunol. 2010 May;11(5):373-84
references: 20404851
references: Cell Microbiol. 2010 Nov;12(11):1622-33
references: 20608941
references: J Biol Chem. 2011 Jan 14;286(2):952-60
references: 21041311
references: Mol Biol Cell. 2008 Aug;19(8):3323-33
references: 18508925
references: Mol Cell Proteomics. 2009 Jan;8(1):201-13
references: 18815123
references: Cell. 2007 Sep 21;130(6):1083-94
references: 17825402
references: Annu Rev Biochem. 2009;78:363-97
references: 19489724
references: J Immunol. 2003 Aug 1;171(3):1515-25
references: 12874245
references: J Biol Chem. 2008 Dec 5;283(49):33858-64
references: 18849341
references: Clin Immunol. 2012 Jun;143(3):207-9
references: 22542741
references: J Immunol. 2010 Jun 1;184(11):5980-7
references: 20439919
references: J Proteome Res. 2012 Jan 1;11(1):237-46
references: 22115061
references: Nat Immunol. 2010 Apr;11(4):335-43
references: 20190759
references: Nature. 2003 Jun 5;423(6940):655-9
references: 12789342
references: Nat Rev Immunol. 2009 Oct;9(10):692-703
references: 19859064
references: Nature. 2003 Jun 5;423(6940):659-63
references: 12789343
references: Mol Cell Biochem. 2009 Dec;332(1-2):113-20
references: 19557502
references: Blood. 2011 Jan 27;117(4):1205-17
references: 20956800
references: PLoS One. 2009;4(3):e4809
references: 19277208
references: EMBO J. 2009 Feb 18;28(4):372-82
references: 19153604
references: Infect Immun. 2001 Mar;69(3):1315-21
references: 11179293