title: Cutting Edge: a novel, human-specific interacting protein couples FOXP3 to a chromatin-remodeling complex that contains KAP1/TRIM28.
abstract: Regulatory T cells (Tregs) play a pivotal role in the maintenance of immunological self-tolerance. Deficiency or dysfunction of Tregs leads to severe autoimmune diseases. Although the forkhead/winged-helix family member FOXP3 is critical for Treg differentiation and function, the molecular basis for FOXP3 function remains unclear. In this study, we identified and characterized a human-specific FOXP3-interacting protein, referred to as FIK (FOXP3-interacting KRAB domain-containing protein). FIK is highly expressed in Tregs and acts as a bridging molecule to link FOXP3 with the chromatin-remodeling scaffold protein KAP1 (TIF-1β/TRIM28). Disruption of the FOXP3-FIK-KAP1 complex in Tregs restored expression of FOXP3-target genes and abrogated the suppressor activity of the Tregs. These data demonstrate a critical role for FIK in regulating FOXP3 activity and Treg function.
authors.affiliation: Immunology Research Program, Benaroya Research Institute, Seattle, WA 98101, USA.
authors.forename: Chunjian
authors.initials: C
authors.lastname: Huang
authors.forename: Sunil
authors.initials: S
authors.lastname: Martin
authors.forename: Christian
authors.initials: C
authors.lastname: Pfleger
authors.forename: Jianguang
authors.initials: J
authors.lastname: Du
authors.forename: Jane H
authors.initials: JH
authors.lastname: Buckner
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
mesh_terms: D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000276:immunology* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D012097:Repressor Proteins / Q000276:immunology* / Q000378:metabolism*; D017634:Self Tolerance / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D002843:Chromatin; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28
references.citation: J Mol Biol. 2000 Feb 4;295(5):1139-62
references.pmid: 10653693
references.citation: Nat Immunol. 2003 Apr;4(4):337-42
references.pmid: 12612581
references.citation: EMBO J. 2003 Apr 15;22(8):1857-67
references.pmid: 12682018
references.citation: Nat Immunol. 2012 Oct;13(10):1010-9
references.pmid: 22922362
references.citation: J Biol Chem. 2011 Jul 29;286(30):26267-76
references.pmid: 21652716
references.citation: Cell. 2000 May 26;101(5):455-8
references.pmid: 10850488
references.citation: J Immunol. 2017 Feb 1;198(3):981-985
references.pmid: 28115586
references.citation: J Immunol. 2008 Apr 1;180(7):4785-92
references.pmid: 18354202
references.citation: J Immunol. 2006 Sep 1;177(5):3133-42
references.pmid: 16920951
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4571-6
references.pmid: 17360565
references.citation: Biol Reprod. 2005 Feb;72(2):407-15
references.pmid: 15469996
references.citation: Mol Cell Biol. 2001 Jun;21(11):3609-15
references.pmid: 11340155
references.citation: Blood. 2012 Apr 12;119(15):3420-30
references.pmid: 22318202
references.citation: Science. 2009 Aug 28;325(5944):1142-6
references.pmid: 19696312
references.citation: Diabetes. 2009 Mar;58(3):652-62
references.pmid: 19074986
references.citation: Nat Immunol. 2003 Apr;4(4):330-6
references.pmid: 12612578
references.citation: Annu Rev Immunol. 2000;18:423-49
references.pmid: 10837065
references.citation: J Immunol. 2008 Aug 15;181(4):2855-68
references.pmid: 18684977
references.citation: J Clin Invest. 2005 Nov;115(11):3276-84
references.pmid: 16211090
references.citation: Nat Immunol. 2012 Apr 29;13(6):596-603
references.pmid: 22544392
references.citation: Genome Biol. 2003;4(10):231
references.pmid: 14519192
references.citation: Nature. 2008 May 8;453(7192):236-40
references.pmid: 18368049
references.citation: Nat Rev Immunol. 2003 Mar;3(3):253-7
references.pmid: 12658273
references.citation: Annu Rev Immunol. 2006;24:209-26
references.pmid: 16551248
references.citation: J Exp Med. 2006 Jul 10;203(7):1701-11
references.pmid: 16818678