title: NF-κB transcriptional activity is modulated by FK506-binding proteins FKBP51 and FKBP52: a role for peptidyl-prolyl isomerase activity.
abstract: Hsp90 binding immunophilins FKBP51 and FKBP52 modulate steroid receptor trafficking and hormone-dependent biological responses. With the purpose to expand this model to other nuclear factors that are also subject to nuclear-cytoplasmic shuttling, we analyzed whether these immunophilins modulate NF-κB signaling. It is demonstrated that FKBP51 impairs both the nuclear translocation rate of NF-κB and its transcriptional activity. The inhibitory action of FKBP51 requires neither the peptidylprolyl-isomerase activity of the immunophilin nor its association with Hsp90. The TPR domain of FKBP51 is essential. On the other hand, FKBP52 favors the nuclear retention time of RelA, its association to a DNA consensus binding sequence, and NF-κB transcriptional activity, the latter effect being strongly dependent on the peptidylprolyl-isomerase activity and also on the TPR domain of FKBP52, but its interaction with Hsp90 is not required. In unstimulated cells, FKBP51 forms endogenous complexes with cytoplasmic RelA. Upon cell stimulation with phorbol ester, the NF-κB soluble complex exchanges FKBP51 for FKBP52, and the NF-κB biological effect is triggered. Importantly, FKBP52 is functionally recruited to the promoter region of NF-κB target genes, whereas FKBP51 is released. Competition assays demonstrated that both immunophilins antagonize one another, and binding assays with purified proteins suggest that the association of RelA and immunophilins could be direct. These observations suggest that the biological action of NF-κB in different cell types could be positively regulated by a high FKBP52/FKBP51 expression ratio by favoring NF-κB nuclear retention, recruitment to the promoter regions of target genes, and transcriptional activity.
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Química Biológica de Ciencias Exactas y Naturales (IQUIBICEN)/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, C1428ADN Argentina.
authors.forename: Alejandra G
authors.initials: AG
authors.lastname: Erlejman
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Química Biológica de Ciencias Exactas y Naturales (IQUIBICEN)/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, C1428ADN Argentina.
authors.forename: Sonia A
authors.initials: SA
authors.lastname: De Leo
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Química Biológica de Ciencias Exactas y Naturales (IQUIBICEN)/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, C1428ADN Argentina.
authors.forename: Gisela I
authors.initials: GI
authors.lastname: Mazaira
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Química Biológica de Ciencias Exactas y Naturales (IQUIBICEN)/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, C1428ADN Argentina.
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Molinari
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Química Biológica de Ciencias Exactas y Naturales (IQUIBICEN)/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, C1428ADN Argentina.
authors.forename: María Fernanda
authors.initials: MF
authors.lastname: Camisay
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Química Biológica de Ciencias Exactas y Naturales (IQUIBICEN)/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, C1428ADN Argentina.
authors.forename: Vanina
authors.initials: V
authors.lastname: Fontana
authors.affiliation: Border Biomedical Research Center and Department of Biological Sciences, University of Texas, El Paso, Texas 79968.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Cox
authors.affiliation: Laboratorio de Arquitectura Nuclear, Instituto de Biología y Medicina Experimental/CONICET, Buenos Aires C1428ADN, Argentina, and.
authors.forename: Graciela
authors.initials: G
authors.lastname: Piwien-Pilipuk
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Química Biológica de Ciencias Exactas y Naturales (IQUIBICEN)/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, C1428ADN Argentina,; Laboratorio de Receptores Nucleares, Instituto de Biología y Medicina Experimental/CONICET, Buenos Aires C1428ADN, Argentina. Electronic address: mgaligniana@conicet.gov.ar.
authors.forename: Mario D
authors.initials: MD
authors.lastname: Galigniana
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000099159:Tacrolimus Binding Protein 5
chemical_list: D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D051996:Transcription Factor RelA; D000099159:Tacrolimus Binding Protein 5; C498143:RELA protein, human; C403485:tacrolimus binding protein 4
keywords: 70-Kilodalton Heat Shock Protein (Hsp70); Chromatin Immunoprecipitation (ChIP); FKBP51; FKBP52; Heat Shock Protein 90 (Hsp90); NF-kappaB (NF-κB); PPIase; Protein Trafficking; Protein Translocation; RelA
references.citation: Biochim Biophys Acta. 2014 Feb;1839(2):71-87
references.pmid: 24389346
references.citation: EMBO J. 2001 Jul 2;20(13):3459-72
references.pmid: 11432833
references.citation: Biochimie. 2001 Mar-Apr;83(3-4):341-9
references.pmid: 11295495
references.citation: J Biol Chem. 2002 Feb 15;277(7):4597-600
references.pmid: 11751894
references.citation: Curr Opin Pharmacol. 2011 Aug;11(4):308-13
references.pmid: 21514887
references.citation: J Biol Chem. 2002 Mar 29;277(13):10842-51
references.pmid: 11801607
references.citation: Mol Cell. 2005 Apr 1;18(1):71-82
references.pmid: 15808510
references.citation: J Cell Biochem. 2004 Jan 1;91(1):100-17
references.pmid: 14689584
references.citation: Hum Reprod. 2012 Jul;27(7):2096-106
references.pmid: 22587999
references.citation: J Biol Chem. 2006 Jul 7;281(27):18684-90
references.pmid: 16675465
references.citation: Mol Cell Biol. 1991 Jan;11(1):259-66
references.pmid: 1986224
references.citation: Oncogene. 2006 Oct 30;25(51):6706-16
references.pmid: 17072323
references.citation: Clin Cancer Res. 2012 Sep 1;18(17):4669-81
references.pmid: 22806876
references.citation: Mol Cell. 2003 Dec;12(6):1413-26
references.pmid: 14690596
references.citation: Trends Cell Biol. 2002 Apr;12(4):164-72
references.pmid: 11978535
references.citation: Nat Cell Biol. 2004 Feb;6(2):97-105
references.pmid: 14743216
references.citation: Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10974-8
references.pmid: 1279700
references.citation: Curr Opin Pharmacol. 2011 Aug;11(4):314-9
references.pmid: 21511531
references.citation: Biochemistry. 2007 Dec 11;46(49):14044-57
references.pmid: 18001136
references.citation: Biochim Biophys Acta. 2013 Sep;1829(9):937-45
references.pmid: 23624258
references.citation: Trends Endocrinol Metab. 2011 Dec;22(12):481-90
references.pmid: 21889356
references.citation: Oncogene. 1999 Nov 22;18(49):6842-4
references.pmid: 10602459
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):868-73
references.pmid: 12538866
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2876-81
references.pmid: 14978266
references.citation: J Clin Endocrinol Metab. 1998 Oct;83(10):3609-14
references.pmid: 9768673
references.citation: Nature. 2004 Apr 8;428(6983):660-4
references.pmid: 15071597
references.citation: Br J Pharmacol. 2012 May;166(2):637-49
references.pmid: 22091865
references.citation: Cell Stress Chaperones. 2010 Mar;15(2):153-63
references.pmid: 19551494
references.citation: J Biol Chem. 2005 Feb 11;280(6):4609-16
references.pmid: 15591061
references.citation: Nucleus. 2010 Jul-Aug;1(4):299-308
references.pmid: 21113270
references.citation: Mol Endocrinol. 2013 Jul;27(7):1020-35
references.pmid: 23686112
references.citation: Mol Endocrinol. 2005 Jun;19(6):1654-66
references.pmid: 15831525
references.citation: J Cell Sci. 2002 Mar 15;115(Pt 6):1137-48
references.pmid: 11884514
references.citation: EMBO J. 2003 Mar 3;22(5):1158-67
references.pmid: 12606580
references.citation: Arch Biochem Biophys. 2008 Aug 15;476(2):186-95
references.pmid: 18275839
references.citation: Eur J Biochem. 1993 Sep 15;216(3):689-707
references.pmid: 8404888
references.citation: Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11086-90
references.pmid: 7479942
references.citation: J Immunol. 2012 Dec 15;189(12):5561-71
references.pmid: 23152563
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14326-31
references.pmid: 16176985
references.citation: J Biol Chem. 2007 Nov 2;282(44):32311-9
references.pmid: 17728246
references.citation: Crit Rev Biochem Mol Biol. 2004 Sep-Dec;39(5-6):279-95
references.pmid: 15763706
references.citation: Am J Reprod Immunol. 2004 Sep;52(3):218-23
references.pmid: 15373762
references.citation: Trends Cell Biol. 2012 Nov;22(11):557-66
references.pmid: 22995730
references.citation: Curr Mol Pharmacol. 2010 Nov;3(3):98-122
references.pmid: 20594187
references.citation: J Cell Biol. 2013 Oct 14;203(1):57-71
references.pmid: 24100296
references.citation: J Pathol. 2006 Sep;210(1):19-25
references.pmid: 16841372
references.citation: J Neurochem. 2010 Nov;115(3):716-34
references.pmid: 20796173
references.citation: Biochim Biophys Acta. 2014 Aug;1840(8):2571-80
references.pmid: 24631662
references.citation: Oncogene. 2010 Mar 18;29(11):1691-701
references.pmid: 20023700
references.citation: J Biol Chem. 2004 May 21;279(21):22483-9
references.pmid: 15004035
references.citation: Biochemistry. 2008 Sep 30;47(39):10471-80
references.pmid: 18771283
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1014-9
references.pmid: 10655476
references.citation: J Mol Histol. 2012 Oct;43(5):487-96
references.pmid: 22714107
references.citation: J Biol Chem. 2001 May 4;276(18):14884-9
references.pmid: 11278753
references.citation: Exp Hematol. 2013 Feb;41(2):209-18
references.pmid: 23063726
references.citation: Eur J Cancer. 2004 Dec;40(18):2829-36
references.pmid: 15571967
references.citation: Biochim Biophys Acta. 2012 Mar;1823(3):722-9
references.pmid: 22155719
references.citation: Oncotarget. 2013 Jan;4(1):35-47
references.pmid: 23296022
references.citation: Oncogene. 2008 Apr 10;27(17):2430-44
references.pmid: 17968310
references.citation: Cold Spring Harb Perspect Biol. 2009 Oct;1(4):a000034
references.pmid: 20066092
references.citation: Mol Cell Biol. 2010 Mar;30(5):1285-98
references.pmid: 20038533
references.citation: Exp Cell Res. 2011 Apr 1;317(6):706-23
references.pmid: 21122806
references.citation: Chem Biol. 2012 Jun 22;19(6):662-3
references.pmid: 22726677
references.citation: Cell Death Dis. 2013 Apr 04;4:e578
references.pmid: 23559012
references.citation: PLoS One. 2013;8(2):e56395
references.pmid: 23437123
references.citation: PLoS One. 2013 Jun 07;8(6):e65280
references.pmid: 23762333
references.citation: Cell. 1986 Aug 29;46(5):705-16
references.pmid: 3091258
references.citation: J Neurochem. 2006 Oct;99(2):402-15
references.pmid: 17029595
references.citation: Placenta. 2000 May;21(4):354-60
references.pmid: 10833370
references.citation: Mol Endocrinol. 2006 Nov;20(11):2682-94
references.pmid: 16873445
references.citation: Nature. 2005 Apr 28;434(7037):1138-43
references.pmid: 15858576
references.citation: PLoS One. 2007 Jul 11;2(7):e589
references.pmid: 17622342
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3588-92
references.pmid: 8386376
references.citation: Curr Med Chem. 2011;18(35):5355-79
references.pmid: 22087830
references.citation: J Biol Chem. 2011 Aug 26;286(34):30152-60
references.pmid: 21730050
references.citation: Mol Cell Biol. 1995 Feb;15(2):943-53
references.pmid: 7823959
references.citation: Int J Cancer. 2004 Dec 20;112(6):1003-9
references.pmid: 15386345
references.citation: Mol Cancer. 2013 Aug 02;12:86
references.pmid: 23915189
references.citation: PLoS One. 2010 Jul 22;5(7):e11717
references.pmid: 20661446
references.citation: Biochemistry. 2007 Feb 6;46(5):1389-97
references.pmid: 17260968