title: CCDC22 deficiency in humans blunts activation of proinflammatory NF-κB signaling.
abstract: NF-κB is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory IκB proteins. In addition, the inactivation of DNA-bound NF-κB is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-κB blockade. Indeed, patient-derived cells demonstrated impaired NF-κB activation due to decreased IκB ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of IκB proteins. Taken together, our results indicate that CCDC22 participates in NF-κB activation and that its deficiency leads to decreased IκB turnover in humans, highlighting an important regulatory component of this pathway.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Petro
authors.initials: P
authors.lastname: Starokadomskyy
authors.forename: Nathan
authors.initials: N
authors.lastname: Gluck
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.forename: Baozhi
authors.initials: B
authors.lastname: Chen
authors.forename: Mathew
authors.initials: M
authors.lastname: Wallis
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Maine
authors.forename: Xicheng
authors.initials: X
authors.lastname: Mao
authors.forename: Iram W
authors.initials: IW
authors.lastname: Zaidi
authors.forename: Marco Y
authors.initials: MY
authors.lastname: Hein
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: McDonald
authors.forename: Steffen
authors.initials: S
authors.lastname: Lenzner
authors.forename: Agnes
authors.initials: A
authors.lastname: Zecha
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
authors.forename: Julie
authors.initials: J
authors.lastname: McGaughran
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Ezra
authors.initials: E
authors.lastname: Burstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D041321:Chromosomes, Human, X; D004476:Ectodermal Dysplasia / Q000378:metabolism; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation; D008856:Microscopy, Fluorescence; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C571908:CCDC22 protein, human; C480519:COMMD1 protein, human; C581993:COMMD8 protein, human; D002352:Carrier Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011506:Proteins; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha
references.citation: Sci Signal. 2013 Jan 15;6(258):rs3
references.pmid: 23322906
references.citation: Genome Biol. 2009;10(11):R130
references.pmid: 19919682
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D225-9
references.pmid: 21109532
references.citation: Hum Mol Genet. 2002 Jan 15;11(2):165-73
references.pmid: 11809725
references.citation: Mol Cell Biol. 2007 Jun;27(11):4142-56
references.pmid: 17371845
references.citation: Nat Genet. 2001 Mar;27(3):277-85
references.pmid: 11242109
references.citation: Nature. 1993 Sep 9;365(6442):182-5
references.pmid: 8371761
references.citation: Mol Cell. 2003 Mar;11(3):571-5
references.pmid: 12667442
references.citation: Genes Dev. 1995 Jul 1;9(13):1586-97
references.pmid: 7628694
references.citation: Mol Cell. 2011 Aug 5;43(3):381-91
references.pmid: 21816345
references.citation: Nat Immunol. 2001 Mar;2(3):223-8
references.pmid: 11224521
references.citation: Science. 1988 Oct 28;242(4878):540-6
references.pmid: 3140380
references.citation: Biochem J. 2006 Aug 15;398(1):63-71
references.pmid: 16573520
references.citation: Oncogene. 2012 Feb 2;31(5):611-23
references.pmid: 21706061
references.citation: Mol Psychiatry. 2012 Jan;17(1):4-7
references.pmid: 21826058
references.citation: Genes Dev. 2009 Apr 1;23(7):849-61
references.pmid: 19339690
references.citation: Cold Spring Harb Protoc. 2009 Nov;2009(11):pdb.prot5318
references.pmid: 20150057
references.citation: J Neurosci. 2011 Apr 6;31(14):5414-25
references.pmid: 21471377
references.citation: J Allergy Clin Immunol. 2010 Jun;125(6):1395-9
references.pmid: 20398921
references.citation: Mol Cell Biol. 2001 Jul;21(13):4292-301
references.pmid: 11390657
references.citation: Nature. 1998 Dec 10;396(6711):590-4
references.pmid: 9859996
references.citation: J Hepatol. 2003 Nov;39(5):703-9
references.pmid: 14568250
references.citation: Biochemistry. 2007 Mar 20;46(11):3116-28
references.pmid: 17309234
references.citation: J Biol Chem. 2005 Jun 10;280(23):22222-32
references.pmid: 15799966
references.citation: J Clin Invest. 2008 Jun;118(6):2088-97
references.pmid: 18464930
references.citation: J Biol Chem. 2004 Feb 13;279(7):5429-34
references.pmid: 14645214
references.citation: EMBO J. 2007 Jan 24;26(2):436-47
references.pmid: 17183367
references.citation: Nature. 2003 Dec 18;426(6968):853-7
references.pmid: 14685242
references.citation: J Clin Invest. 2011 Dec;121(12):4889-902
references.pmid: 22105173
references.citation: J Biol Chem. 2011 Sep 16;286(37):32355-65
references.pmid: 21778237
references.citation: Am J Physiol Renal Physiol. 2010 Jun;298(6):F1445-56
references.pmid: 20237237
references.citation: Nature. 1995 Feb 9;373(6514):531-6
references.pmid: 7845467
references.citation: Genes Dev. 1995 Aug 15;9(16):1965-77
references.pmid: 7649478
references.citation: Nat Methods. 2008 May;5(5):409-15
references.pmid: 18391959
references.citation: EMBO Rep. 2009 Apr;10(4):381-6
references.pmid: 19270718
references.citation: Cell. 1995 Jan 27;80(2):321-30
references.pmid: 7834752
references.citation: Biochem Biophys Res Commun. 2011 Aug 5;411(3):506-11
references.pmid: 21741370
references.citation: Hum Genet. 1986 Aug;73(4):320-6
references.pmid: 3017841
references.citation: Nat Rev Cancer. 2008 Jun;8(6):438-49
references.pmid: 18500245
references.citation: Mol Cell Proteomics. 2008 Mar;7(3):499-508
references.pmid: 18029348
references.citation: Mol Cell Biol. 1997 Mar;17(3):1535-42
references.pmid: 9032281
references.citation: Mol Cell Biol. 1998 Jan;18(1):608-15
references.pmid: 9418907
references.citation: J Clin Invest. 2010 Jun;120(6):2119-30
references.pmid: 20458141
references.citation: Development. 2001 Oct;128(19):3843-53
references.pmid: 11585809
references.citation: PLoS One. 2011 Mar 31;6(3):e18334
references.pmid: 21483833
references.citation: Nat Rev Mol Cell Biol. 2005 Jan;6(1):9-20
references.pmid: 15688063
references.citation: Nat Neurosci. 2011 Apr;14(4):437-41
references.pmid: 21423191
references.citation: J Cell Biol. 2010 May 17;189(4):739-54
references.pmid: 20479470
references.citation: Cell. 2008 Feb 8;132(3):344-62
references.pmid: 18267068
references.citation: Am J Med Genet A. 2009 Sep;149A(9):2031-6
references.pmid: 19681132
references.citation: Clin Microbiol Rev. 2011 Jul;24(3):490-7
references.pmid: 21734245
references.citation: EMBO J. 2004 Jan 14;23(1):244-54
references.pmid: 14685266
references.citation: Nat Neurosci. 2003 Oct;6(10):1072-8
references.pmid: 12947408