title: Jun activation domain-binding protein 1 (JAB1) is required for the optimal response to interferons.
abstract: Degradation of IFN receptor (IFNR) protein is one of the mechanisms to limit the extent of cellular responses to interferons. Tyrosine kinase 2 (TYK2), a JAK family kinase, has been reported to bind to and stabilize IFNR, indicating that TYK2 is a fundamental component of IFNR complex. Herein, we identified Jun activation domain-binding protein 1 (JAB1) as a new TYK2 binding partner and investigated its role in the regulation of IFN responses. siRNA knockdown of JAB1 resulted in suppression of IFN-induced phosphorylation of STAT proteins and their transcriptional activation. Importantly, JAB1 knockdown induced the activation of SCF ubiquitin ligase complex containing Cullin 1 (CUL1), as judged by the enhancement of covalent modification of CUL1 with the ubiquitin-like protein NEDD8, and markedly reduced the basal protein level of IFNR. In contrast, NEDD8 knockdown or inhibition of NEDD8 modification by NEDD8-activating enzyme inhibitor resulted in increased IFNR protein concomitantly with a reduction of NEDD8-modified CUL1. Furthermore, NEDD8-activating enzyme inhibitor treatment enhanced the susceptibility to IFN-α in HeLa cells. These data suggest that the NEDD8 modification pathway is involved in the proteolysis of IFNR and that JAB1 acts as a positive regulator of IFN responses by stabilizing IFNR through antagonizing the NEDD8 pathway.
authors.affiliation: From the Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-Ku, Sapporo 060-0812, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Muromoto
authors.forename: Maiko
authors.initials: M
authors.lastname: Nakajima
authors.forename: Koki
authors.initials: K
authors.lastname: Hirashima
authors.forename: Toru
authors.initials: T
authors.lastname: Hirao
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kon
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.forename: Kenji
authors.initials: K
authors.lastname: Oritani
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000075686:COP9 Signalosome Complex; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D000075687:NEDD8 Protein; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D007155:Immunologic Factors; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D017471:Receptors, Interferon; D014452:Ubiquitins; D044843:SKP Cullin F-Box Protein Ligases; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex
keywords: Cytokine; Interferon; JAK Kinase; Post-translational Modification; Protein Degradation; Receptor Regulation; Signal Transduction; Tyrosine-Protein Kinase (Tyrosine Kinase)
references.citation: Trends Biochem Sci. 2008 Dec;33(12):592-600
references.pmid: 18926707
references.citation: J Immunol. 2004 Mar 1;172(5):2985-93
references.pmid: 14978102
references.citation: FEBS Lett. 2006 Jan 9;580(1):93-8
references.pmid: 16364321
references.citation: Mol Cell Biol. 2004 Aug;24(16):7130-9
references.pmid: 15282312
references.citation: Cell Host Microbe. 2009 Jan 22;5(1):72-83
references.pmid: 19154989
references.citation: Immunol Rev. 2004 Dec;202:8-32
references.pmid: 15546383
references.citation: Nat Immunol. 2007 Nov;8(11):1236-45
references.pmid: 17906629
references.citation: Cancer Res. 2010 Dec 15;70(24):10310-20
references.pmid: 21159650
references.citation: Cell. 2003 Sep 19;114(6):663-71
references.pmid: 14505567
references.citation: Science. 2002 Oct 18;298(5593):608-11
references.pmid: 12183637
references.citation: Annu Rev Immunol. 2008;26:317-53
references.pmid: 18304004
references.citation: Biochem Biophys Res Commun. 2003 Feb 7;301(2):392-8
references.pmid: 12565873
references.citation: Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):11839-44
references.pmid: 9342324
references.citation: Mol Cell Biol. 2000 Nov;20(21):8185-97
references.pmid: 11027288
references.citation: Biochim Biophys Acta. 2004 Nov 29;1695(1-3):133-70
references.pmid: 15571813
references.citation: Nat Cell Biol. 2003 Dec;5(12):1029-33
references.pmid: 14647295
references.citation: Nat Rev Mol Cell Biol. 2004 Sep;5(9):739-51
references.pmid: 15340381
references.citation: J Exp Med. 2003 Dec 15;198(12):1829-39
references.pmid: 14676297
references.citation: Science. 2001 May 18;292(5520):1382-5
references.pmid: 11337588
references.citation: EMBO J. 2003 Oct 15;22(20):5480-90
references.pmid: 14532120
references.citation: J Biol Chem. 2001 Aug 17;276(33):30812-8
references.pmid: 11399767
references.citation: Nature. 2009 Apr 9;458(7239):732-6
references.pmid: 19360080
references.citation: J Immunol. 2004 Jul 15;173(2):1151-7
references.pmid: 15240704
references.citation: J Biol Chem. 1997 Apr 4;272(14):9086-92
references.pmid: 9083035
references.citation: J Virol. 1998 Oct;72(10):8150-7
references.pmid: 9733856
references.citation: Immunity. 2012 Apr 20;36(4):503-14
references.pmid: 22520844
references.citation: Science. 2001 May 18;292(5520):1379-82
references.pmid: 11337587
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9946-51
references.pmid: 12902539
references.citation: J Biol Chem. 2003 Dec 26;278(52):52865-72
references.pmid: 14563850
references.citation: J Biol Chem. 2008 Jul 4;283(27):18566-72
references.pmid: 18474601
references.citation: EMBO J. 2007 Mar 21;26(6):1532-41
references.pmid: 17318178
references.citation: Biochem Biophys Res Commun. 2008 Mar 7;367(2):388-93
references.pmid: 18166147
references.citation: Mol Cell. 2008 Oct 10;32(1):21-31
references.pmid: 18851830
references.citation: Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9602-6
references.pmid: 7524081
references.citation: J Biol Chem. 2000 Oct 13;275(41):32317-24
references.pmid: 10921923
references.citation: J Biol Chem. 2006 Oct 27;281(43):32188-96
references.pmid: 16943200
references.citation: J Cell Biol. 2007 Dec 3;179(5):935-50
references.pmid: 18056411
references.citation: Cancer Res. 2011 Apr 15;71(8):3042-51
references.pmid: 21487042
references.citation: Cancer Res. 2013 Jan 1;73(1):225-34
references.pmid: 23100467
references.citation: J Neuroimmunol. 2013 Jan 15;254(1-2):101-9
references.pmid: 23110939
references.citation: EMBO Rep. 2009 Jun;10(6):642-8
references.pmid: 19444310
references.citation: Clin Cancer Res. 2009 Jun 15;15(12):3912-6
references.pmid: 19509147
references.citation: Science. 1994 Jun 24;264(5167):1918-21
references.pmid: 8009221
references.citation: J Immunol. 2006 Jul 15;177(2):1160-70
references.pmid: 16818774
references.citation: Immunity. 2006 Nov;25(5):745-55
references.pmid: 17088085
references.citation: Annu Rev Cell Dev Biol. 2003;19:261-86
references.pmid: 14570571
references.citation: BMC Cell Biol. 2009 Apr 28;10:31
references.pmid: 19400951
references.citation: Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11284-8
references.pmid: 7479980
references.citation: EMBO J. 2003 Feb 3;22(3):537-47
references.pmid: 12554654
references.citation: Mol Cell Biol. 2000 Apr;20(7):2326-33
references.pmid: 10713156
references.citation: Biochim Biophys Acta. 2004 Nov 29;1695(1-3):45-54
references.pmid: 15571808
references.citation: Nat Rev Mol Cell Biol. 2005 Jan;6(1):9-20
references.pmid: 15688063
references.citation: J Biol Chem. 2010 Jan 22;285(4):2318-25
references.pmid: 19948722
references.citation: PLoS One. 2009 Dec 17;4(12):e8342
references.pmid: 20020050