NIBP, a Novel NIK and IKKβ-binding Protein That Enhances NF-κB Activation

Abstract

The transcription factor NF-κB plays an important role in both physiological and pathological events in the central nervous system. Nevertheless, the mechanisms of NF-κB-mediated regulation of gene expression, and the signaling molecules participating in the NF-κB pathway in the central nervous system are, to date, poorly understood. To identify such molecules, we conducted a yeast two-hybrid screen of a human brain cDNA library using NIK as bait. As a result, we identified a novel NIK and IKKβ binding protein designated NIBP that is mainly expressed in brain, muscle, heart, and kidney. Interestingly, low levels of expression were detected in immune tissues such as spleen, thymus, and peripheral blood leukocytes, where NF-κB is known to modulate immune function. We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKKβ, but not IKKα or IKKγ. NIBP overexpression potentiates tumor necrosis factor-α-induced NF-κB activation through increased phosphorylation of the IKK complex and its downstream IκBα and p65 substrates. Finally, knockdown of NIBP expression by small interfering RNA reduces tumor necrosis factor-α-induced NF-κB activation, prevents nerve growth factor-induced neuronal differentiation, and decreases Bcl-xL gene expression in PC12 cells. Our data demonstrate that NIBP, by interacting with NIK and IKKβ, is a new enhancer of the cytokine-induced NF-κB signaling pathway. Because of its neuronal expression, we propose that NIBP may be a potential target for modulating the NF-κB signaling cascade in neuronal pathologies dependent upon abnormal activation of this pathway. The transcription factor NF-κB plays an important role in both physiological and pathological events in the central nervous system. Nevertheless, the mechanisms of NF-κB-mediated regulation of gene expression, and the signaling molecules participating in the NF-κB pathway in the central nervous system are, to date, poorly understood. To identify such molecules, we conducted a yeast two-hybrid screen of a human brain cDNA library using NIK as bait. As a result, we identified a novel NIK and IKKβ binding protein designated NIBP that is mainly expressed in brain, muscle, heart, and kidney. Interestingly, low levels of expression were detected in immune tissues such as spleen, thymus, and peripheral blood leukocytes, where NF-κB is known to modulate immune function. We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKKβ, but not IKKα or IKKγ. NIBP overexpression potentiates tumor necrosis factor-α-induced NF-κB activation through increased phosphorylation of the IKK complex and its downstream IκBα and p65 substrates. Finally, knockdown of NIBP expression by small interfering RNA reduces tumor necrosis factor-α-induced NF-κB activation, prevents nerve growth factor-induced neuronal differentiation, and decreases Bcl-xL gene expression in PC12 cells. Our data demonstrate that NIBP, by interacting with NIK and IKKβ, is a new enhancer of the cytokine-induced NF-κB signaling pathway. Because of its neuronal expression, we propose that NIBP may be a potential target for modulating the NF-κB signaling cascade in neuronal pathologies dependent upon abnormal activation of this pathway. NF-κB is a multipotent transcription factor that regulates the expression of numerous genes involved in a wide array of biological responses such as inflammation, immunity, apoptosis, and synaptic plasticity (1Shishodia S. Aggarwal B.B. Biochem. Pharmacol. 2004; 68: 1071-1080Crossref PubMed Scopus (228) Google Scholar, 2Kucharczak J. Simmons M.J. Fan Y. Gelinas C. Oncogene. 2003; 22: 8961-8982Crossref PubMed Scopus (682) Google Scholar, 3Weih F. Caamano J. Immunol. Rev. 2003; 195: 91-105Crossref PubMed Scopus (187) Google Scholar, 4Mattson M.P. Culmsee C. Yu Z. Camandola S. J. Neurochem. 2000; 74: 443-456Crossref PubMed Scopus (436) Google Scholar). In mammals, the NF-κB family of transcription factors consists of five members: p65 (or RelA), RelB, c-Rel, NF-κB1 (or p105, precursor of p50), and NF-κB2 (or p100, precursor of p52). To date, two principal pathways for NF-κB activation have been characterized, a classical and an alternative pathway (5Patke A. Mecklenbrauker I. Tarakhovsky A. Curr. Opin. Immunol. 2004; 16: 251-255Crossref PubMed Scopus (53) Google Scholar, 6Perkins N.D. Oncogene. 2003; 22: 7553-7556Crossref PubMed Scopus (30) Google Scholar, 7Bonizzi G. Karin M. Trends Immunol. 2004; 25: 280-288Abstract Full Text Full Text PDF PubMed Scopus (2138) Google Scholar). The classical pathway is triggered by stimuli such as tumor necrosis factor α (TNFα), 1The abbreviations used are: TNFα, tumor necrosis factor α; NF-κB, nuclear factor κB; NIK, NF-κB inducing kinase; IKK, IκB kinase; IL-1, interleukin-1; TRAF2, tumor necrosis factor receptor-associated factor-2; NGF, nerve growth factor; GST, glutathione S-transferase; siRNA, small interfering RNA; MAP, mitogen-activated protein. IL-1, CD40 ligand, and lymphotoxin-β (8Dejardin E. Droin N.M. Delhase M. Haas E. Cao Y. Makris C. Li Z.W. Karin M. Ware C.F. Green D.R. Immunity. 2002; 17: 525-535Abstract Full Text Full Text PDF PubMed Scopus (787) Google Scholar). Activation of this pathway depends on the IκB kinase (IKK) signalsome, which consists of at least two catalytic subunits (IKKα or IKK1, and IKKβ or IKK2) and a regulatory subunit (IKKγ or NEMO). The activated IKK complex phosphorylates the inhibitor proteins of NF-κB (IκBs) to induce their ubiquitination and degradation, resulting in the translocation of NF-κB dimers (mainly p65/p50) to the nucleus and transcriptional activation of specific target genes. This pathway is crucial for the activation of innate immunity and inflammation. The alternative pathway is activated by lymphotoxin-β (8Dejardin E. Droin N.M. Delhase M. Haas E. Cao Y. Makris C. Li Z.W. Karin M. Ware C.F. Green D.R. Immunity. 2002; 17: 525-535Abstract Full Text Full Text PDF PubMed Scopus (787) Google Scholar, 9Mordmuller B. Krappmann D. Esen M. Wegener E. Scheidereit C. EMBO Rep. 2003; 4: 82-87Crossref PubMed Scopus (107) Google Scholar, 10Muller J.R. Siebenlist U. J. Biol. Chem. 2003; 278: 12006-12012Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar), CD40 ligand (11Coope H.J. Atkinson P.G. Huhse B. Belich M. Janzen J. Holman M.J. Klaus G.G. Johnston L.H. Ley S.C. EMBO J. 2002; 21: 5375-5385Crossref PubMed Scopus (373) Google Scholar), and B cell-activating factor (12Kayagaki N. Yan M. Seshasayee D. Wang H. Lee W. French D.M. Grewal I.S. Cochran A.G. Gordon N.C. Yin J. Starovasnik M.A. Dixit V.M. Immunity. 2002; 17: 515-524Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar). It relies on the phosphorylation of IKKα homodimers by NF-κB inducing kinase (NIK) to induce p100 processing and nuclear translocation of RelB/p52 dimers (7Bonizzi G. Karin M. Trends Immunol. 2004; 25: 280-288Abstract Full Text Full Text PDF PubMed Scopus (2138) Google Scholar). This alternative pathway is necessary for secondary lymphoid organ development, maturation of B cells, and adaptive humoral immunity. NF-κB is involved in the regulation of both physiological and pathological processes. Synaptic stimulation activates NF-κB, which then participates in long-term potentiation, a process associated with memory formation (13Lynch M.A. Physiol. Rev. 2004; 84: 87-136Crossref PubMed Scopus (1504) Google Scholar). In addition, NF-κB has anti-apoptotic properties in neurons because blocking its activation increases their sensitivity to TNFα-induced apoptosis (14Wang C.Y. Mayo M.W. Korneluk R.G. Goeddel D.V. Baldwin Jr., A.S. Science. 1998; 281: 1680-1683Crossref PubMed Scopus (2592) Google Scholar, 15Chen C. Edelstein L.C. Gelinas C. Mol. Cell. Biol. 2000; 20: 2687-2695Crossref PubMed Scopus (700) Google Scholar). Induction of NF-κB is also associated with several neurological diseases such as Parkinsons (16Hunot S. Brugg B. Ricard D. Michel P.P. Muriel M.P. Ruberg M. Faucheux B.A. Agid Y. Hirsch E.C. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7531-7536Crossref PubMed Scopus (642) Google Scholar), Alzheimers (17Bales K.R. Du Y. Holtzman D. Cordell B. Paul S.M. Neurobiol. Aging. 2000; 21: 427-432Crossref PubMed Scopus (126) Google Scholar), AIDS dementia (18Rattner A. Korner M. Walker M.D. Citri Y. 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NIK was originally identified as a serine/threonine protein kinase related to the mitogen-activated protein kinase (MAP3K) that interacts with TNF receptor-associated factor 2 (TRAF2), IKKα, IKKβ, and can strongly activate NF-κB following TNF/NGF receptor family stimulation (22Malinin N.L. Boldin M.P. Kovalenko A.V. Wallach D. Nature. 1997; 385: 540-544Crossref PubMed Scopus (1173) Google Scholar). Although earlier overexpression studies using mutant NIK pointed to a crucial role for NIK in TNFα-induced NF-κB activation, later studies using NIK knock-out mice challenged this view, finding NIK to be an essential component only of the alternative pathway. More recent data, however, indicated that NIK participates in signaling events initiated by specific inducers that activate both the classical and alternative pathways (23Ramakrishnan P. Wang W. Wallach D. Immunity. 2004; 21: 477-489Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar). The first demonstration of the function of NIK in the central nervous system was the observation that Aly mice, in which a naturally occurring mutation in the alymphoplasia allele causes NIK to be non-functional, displayed progressive neurological abnormalities leading to hind limb paralysis (24Miyawaki S. Nakamura Y. Suzuka H. Koba M. Yasumizu R. Ikehara S. Y. J. Immunol. PubMed Scopus Google Scholar). in PC12 cells, NIK formation and prevents apoptosis J. C. R. A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Nevertheless, the regulatory mechanisms of NIK in of the NF-κB signaling pathway in the central nervous system not understood. To we a yeast two-hybrid screen of a brain cDNA library with NIK as bait. As a result, we identified a novel protein designated NIBP NIK and IKKβ binding which interacts with NIK and IKKβ and is expressed in neurons. NIBP functions as an enhancer of NF-κB activation and IKK kinase Finally, in studies that NIBP may be a of Bcl-xL gene expression as as neuronal differentiation, because is for in PC12 cells. two-hybrid was with the The the of NIK, was the binding in the yeast expression as R. J.R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The yeast was with by the expression that a human brain cDNA library to the and TNFα, and as as and were NIK, and p65 were IKKα, NIK, and IκBα were to of NIBP and was used as an to in The NIBP was and its was by and and were expression TRAF2, NIK, IKKα, IKKβ, and were H. Goeddel D.V. Cell. 84: Full Text Full Text PDF PubMed Scopus Google Scholar, D.R. Goeddel D.V. Immunity. 1997; 6: Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). NIBP was by a cDNA library and the expression La The of NIBP was by and a D.R. Goeddel D.V. Immunity. 1997; 6: Full Text Full Text PDF PubMed Scopus Google Scholar). expression of NIBP was by of a human 2 of RNA with a were conducted in the at for 2 to the The were then and with a as brain and spinal cord were with was with using the to and were in essential and were in with and neurons were as J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). were with of by the of NIBP was the expression to a which was with in NIK, IKKα, and In was with the in the of IKKβ the was by In was at with expressed proteins to of proteins were with on a and detected by and and were to as Yan J.R. J. Neurochem. 2002; PubMed Scopus Google Scholar). gene for the of and was with the to the was to were conducted in data were as the of were to R.G. PubMed Scopus Google Scholar). were as (20Bethea J.R. Castro M. Keane R.W. Lee T.T. Dietrich W.D. Yezierski R.P. J. Neurosci. 1998; 18: 3251-3260Crossref PubMed Google Scholar). NF-κB were with kinase and to binding in the of and nuclear of to were in binding a at were a and at for were then and and and NIBP were using a A.V. C. L. J. L. 2003; PubMed Scopus Google Scholar, R. Mol. Biol. 2004; Google Scholar). and NIBP were the of the for NIBP and of NIBP were and of was as A.V. C. L. J. L. 2003; PubMed Scopus Google Scholar). PC12 were with for to were on at a of were with the of protein in was RNA was with the of RNA was used to cDNA using with was on the cDNA using specific for Bcl-xL and and and A. J. Biol. PubMed Scopus Google Scholar). and of the regulatory mechanisms NF-κB signaling in the central nervous we a yeast two-hybrid screen of a human brain cDNA library using as for the of NIK yeast were both and of the the of several known gene for proteins as NIK interacting G. M. S.C. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google and Goeddel D.V. M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google In addition, several novel were of is a of cytokine-induced NF-κB activation R. J.R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). In the we the of a of a novel that NIBP is to the function of which not been NIBP, a is on and a of with and of human tissues indicated that NIBP is expressed at levels in and and at levels in brain, heart, and least two were detected in muscle, and heart, that two or of NIBP may Interestingly, NIBP were or only in immune and such as thymus, spleen, and peripheral blood leukocytes, where the NF-κB signaling pathway is known to regulatory of brain and spinal cord with an a and human NIBP indicated the of NIBP in neuronal cells. NIBP was in both the and of neurons of the of the and in spinal cord neurons and and neurons not NIBP was also detected in neurons and with the NIBP with NIK and IKKβ and but IKKα or the NIBP and NIK in a NIK and NIBP were in cells. As in was with NIK, that interacting in the signaling Because NIK interacts with and activates the IKK complex Goeddel D.V. M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar, Cao Z. M. Goeddel D.V. Science. 1997; 278: PubMed Scopus Google Scholar), we the that NIBP also with subunits of the IKK of with and or that NIBP interacts strongly with IKKβ, with IKKα, and not with The IKKβ and NIBP also be detected in brain following with the NIK was also to with NIBP the in the overexpression system was detected with IKKα or that the detected NIBP and IKKα in be an of the overexpression system. It is that we NIK in brain only following with NIBP NIBP was also detected following of brain with an and two We that the NIBP and be because of an with IKKα, because NIBP was detected brain was with a specific In of the physiological of such were in such as in PC12 and not using the we that NIBP binding to NIK and IKKβ is Interestingly, appears that the NIK and NIBP is in the of IKKβ Finally, binding was detected with IKKα or in with in brain regulates gene expression and in PC12 cells. PC12 were with an or and by with and NIBP with IKKβ and NIK, but not with IKKα or IKKγ. PC12 were with or and by with Bcl-xL gene expression was by in PC12 in the or of The gene was as a and PC12 were with following was by in NIBP NF-κB the specific function of NIBP the NF-κB we the that NIBP regulates cytokine-induced NF-κB activation by its with IKKβ, a in this pathway M. Y. Wang Rev. 2004; PubMed Scopus Google Scholar). TNFα-induced NF-κB activation was in NIBP and a specific NIBP overexpression in not levels of NF-κB in with of NIBP NF-κB were following with not NIBP not gene expression, that the of gene expression by NIBP is specific to the NF-κB pathway The of NIBP to TNFα-induced NF-κB activation was by NF-κB binding was increased in the of NIBP with with a at and This with an increased of the inhibitor of NF-κB, at the of data demonstrated that overexpression of NIBP cytokine-induced NF-κB To NIBP NF-κB activation, we NIBP expression using a We the and of To the and of the were with and and NIBP expression were the and both and expression of NIBP in on this result, we used the in knockdown of NIBP TNFα-induced gene expression Because NF-κB activation through the we which of this pathway were the of NIBP by proteins in where NIBP expression was by of NIBP and NF-κB activation that NIBP the function of NIK and because IKKβ is downstream of TRAF2, NF-κB activation was also Because overexpression of IKKα not NF-κB activation, we NIBP its function To demonstrate that NIBP the function of NIK and the IKK we the of phosphorylation of IκBα and which downstream of in the cytokine-induced NF-κB activation pathway H. H. H. T. W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, N. K. T. T. T. Biochem. 2003; PubMed Scopus Google Scholar). of NIBP and phosphorylation of IκBα and p65 In addition, we IκBα and p65 phosphorylation following overexpression of IKKα, IKKβ, or IKKα overexpression not induce IκBα phosphorylation in the or of NIBP in with the gene data In overexpression of IKKβ IκBα which was in the of NIBP This is in with that the of NIBP strongly reduces NF-κB activation IKKα and IKKβ activated IκBα phosphorylation This was in the of NIBP, to a with IKKβ This be because of an of IKKα on IKKβ kinase A. R. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar). IKKα overexpression p65 phosphorylation only with NIBP In this NIBP be IKKβ NIK, which be for p65 phosphorylation H. H. H. T. W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, I. A. C. R.P. H. T. M. J. Immunol. 2004; PubMed Scopus Google Scholar). As I. A. C. R.P. H. T. M. J. Immunol. 2004; PubMed Scopus Google Scholar), overexpression of IKKβ p65 phosphorylation This was by of NIBP, that NIBP may a role in modulating IKKβ kinase IKKα and IKKβ a of p65 phosphorylation expressed a the two We were to in phosphorylation of p65 in the of NIBP, because of a of the system Because has been that IKK kinase is dependent on the phosphorylation of the activation of IKKα and IKKβ U. Cao Y. G. G. G. Y. Y. A. S.C. Karin M. Science. PubMed Scopus Google Scholar, M. M. Y. Karin M. Science. PubMed Scopus Google Scholar), we this was the of of IKK kinase We IKKα and IKKβ phosphorylation with a the activation of in IKKα, IKKβ, or IKKα overexpression not induce IKKα IKKβ overexpression IKKβ phosphorylation M. M. Y. Karin M. Science. PubMed Scopus Google IKKα and IKKβ were an in phosphorylation of both IKKα and IKKβ was A. R. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google of IKKα with NIBP on the phosphorylation of IKKα IKKα and IKKβ displayed an increased phosphorylation with NIBP We the of NIBP on the phosphorylation of IKKα and In the of NIBP increased the phosphorylation of IKKα and IKKβ with a in IKKα and IKKβ phosphorylation that was in the of NIBP data that NIBP may be such as NIK to the IKK and an protein. Interestingly, studies in the central nervous system indicated that NIBP is expressed in neurons that NIBP perform a function in the neuronal NF-κB signaling pathway. To this we a of in the PC12 neuronal that NIBP a and As demonstrated in and brain NIBP interacts with both IKKβ and NIK in PC12 on recent studies the of NIK and NF-κB in PC12 and J. C. R. A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. Biol. PubMed Scopus Google Scholar, A. R. J. Neurosci. 2000; 20: PubMed Google Scholar, Culmsee C. E. M. J. J. Neurochem. 2002; PubMed Scopus Google Scholar), we NIBP function in PC12 gene expression and that the NIBP protein expression we the expression of a gene by and known to be by NF-κB in PC12 cells. As knockdown of NIBP Bcl-xL gene expression, which was following overexpression of NIBP In cells, overexpression of NIBP the of data that NIBP functions as a downstream component of the pathway in PC12 cells. knockdown of NIBP with the The which reduces but not NIBP expression also PC12 the which not NIBP expression on PC12 Although NF-κB was and as a transcription factor for gene expression, studies demonstrated that is expressed and as a of the expression of a wide of genes in and In recent a of has implicated NF-κB in the regulation of both physiological and pathological in the central nervous system M.P. Camandola S. J. PubMed Scopus Google Scholar, M. M. Biochem. Pharmacol. PubMed Scopus Google Scholar, M.P. Neurosci. 2003; 6: PubMed Scopus Google Scholar). Nevertheless, is known the specific regulatory mechanisms of NF-κB function in this system. To this we used a yeast two-hybrid and identified NIBP, a novel NF-κB regulatory which interacts with NIK and IKKβ and is for cytokine-induced NF-κB with both and expressed NIBP demonstrated the of NIBP not only with NIK, originally as in the yeast two-hybrid but also with IKKβ, of the of the IKK was detected with IKKα or IKKγ. at a role of NIBP in the regulation of the classical NF-κB in upon IKKβ is activated and phosphorylates IκB proteins NF-κB dimers to the nucleus S. 2004; 18: PubMed Scopus Google Scholar). To this we demonstrated that NIBP is necessary for TNFα-induced NF-κB activation, which the of the classical NF-κB signaling cascade (7Bonizzi G. Karin M. Trends Immunol. 2004; 25: 280-288Abstract Full Text Full Text PDF PubMed Scopus (2138) Google Scholar). NIBP expression is TNFα-induced gene expression is as is the phosphorylation of IκBα and two downstream of This that NIBP the function of IKKβ by its kinase Interestingly, the of NIBP with NIK is in the of IKKβ, that proteins of the This to that NIBP may as a protein and with of the NF-κB signaling cascade that we have not NIBP functions with several molecules of the IKK complex that have been identified L. Nature. 1998; PubMed Scopus Google Scholar), A. F. Science. 2004; PubMed Scopus Google Scholar), and S.M. Mol. Cell. Biol. 2003; PubMed Scopus Google In to and however, NIBP not with IKKα and IKKγ. This may that the role of NIBP as a is and that NIBP is to the NF-κB signaling cascade only following stimuli in specific NIBP not to with IKKα or to its kinase we the of a role of NIBP in the regulation of the alternative pathway. To this we NIBP function following stimulation with known of the alternative pathway B cell-activating factor and Interestingly, NIBP is only at low levels in immune in which NF-κB is known to perform important biological the is expressed in such as muscle, heart, and It is to that NIBP expression in the central nervous system appears to be to a function for this protein in the of NF-κB signaling in this to a such as the NF-κB to specific molecules and expressed in on we that NIBP such the neuronal NF-κB signaling cascade to to the activation of NF-κB in the central nervous system. NIBP is necessary for in PC12 this The of NIBP prevents the of PC12 to to NGF, that NIBP is an essential component of the signaling for this specific function. Our in with earlier studies by and J. C. R. A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), that PC12 is dependent on NF-κB and on NIK activation, which in to downstream phosphorylation and activation of the pathway. on this we can that NIBP participates in this by interacting with NIK and IKKβ and by the pathway. To the role of NIBP in PC12 cells, we its to modulate the expression of the anti-apoptotic gene Bcl-xL is for the of peripheral and central neurons and its in PC12 following is dependent upon NF-κB activation A. J. Biol. PubMed Scopus Google Scholar). both overexpression and knockdown we demonstrated that NIBP is for Bcl-xL gene expression in PC12 cells. This an essential role of NIBP the NF-κB pathway not only in the but also the of cells, leading to that functions may be by NIBP in in neuronal we be to functions in an which is in of such a we to NF-κB regulatory mechanisms in neurons. This be a as NF-κB has been implicated in the of We and for We M. and S. for and