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J. Biol. Chem., Vol. 280, Issue 11, 9765-9768, March 18, 2005

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Essential Role of IB Kinase in the Constitutive Processing of NF-B2 p100^*

Guoliang Qing and Gutian Xiao

From the Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854

Received for publication, October 22, 2004 , and in revised form, January 14, 2005.

	ABSTRACT

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Processing of NF-B2 precursor protein p100 to generate p52 is tightly controlled, which is important for proper function of NF-B. Accordingly, constitutive processing of p100, caused by the loss of its C-terminal processing inhibitory domain due to nfb2 gene rearrangements, is associated with the development of various lymphomas and leukemia. In contrast to the physiological processing of p100 triggered by NF-B-inducing kinase (NIK) and its downstream kinase, IB kinase (IKK), which requires the E3 ligase, -transducin repeat-containing protein (-TrCP), and occurs only in the cytoplasm, the constitutive processing of p100 is independent of -TrCP but rather is regulated by the nuclear shuttling of p100. Here, we show that constitutive processing of p100 also requires IKK, but not IKK (IB kinase ) or IKK (IB kinase ). It seems that NIK is also dispensable for this pathogenic processing of p100. These results demonstrate a general role of IKK in p100 processing under both physiological and pathogenic conditions. Additionally, we find that IKK is not required for the nuclear translocation of p100. Thus, these results also indicate that p100 nuclear translocation is not sufficient for the constitutive processing of p100.

	INTRODUCTION

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NF-B represents a collection of dimeric transcription factors composed of members of the Rel family with five closely related DNA binding proteins: RelA (p65), RelB, c-Rel, NF-B1/p50, and NF-B2/p52 (1–3). Whereas the three Rel proteins are synthesized directly as mature proteins, p50 and p52 are generated by proteolytical processing from their large precursors p105 and p100, respectively (4, 5). In resting cells, NF-B dimers are sequestered in the cytoplasm as latent complexes with a family of ankyrin repeat domain-containing inhibitors called IB proteins (1–3). Interestingly, both p105 and p100 contain ankyrin repeats at their C-terminal regions and function as IB-like inhibitors of NF-B (6, 7). Whereas the IB degradation and p100 processing are inducible, the processing of p105 is constitutive (8, 9). Accordingly, the signaling leading to NF-B activation can be classified into two major pathways, the canonical and non-canonical NF-B pathways, which are based on inducible IB degradation and p100 processing, respectively (10).

The canonical NF-B pathway is required for fundamental functions of various cells and can be rapidly and transiently activated by a plethora of substances, such as mitogens, cytokines, and microbial components (11). These stimuli ultimately lead to activation of a specific IB kinase (IKK)¹ complex composed of two catalytic subunits, IKK (IKK1) and IKK (IKK2), and a regulatory subunit, IKK (NEMO) (10). Once activated, IKK phosphorylates specific serines within the IB proteins, triggering their ubiquitination by the -TrCP ubiquitin ligase and degradation by the 26 S proteasome, thus allowing the NF-B dimers to move to the nucleus to induce gene expression (10). Whereas IB degradation predominantly depends on IKK and IKK, IKK is largely dispensable for this event (10), although the nuclear function of IKK is necessary for the transcription activity of NF-B (12, 13).

In contrast, activation of the non-canonical NF-B pathway is strictly dependent on the IKK and its activator NF-B-inducing kinase (NIK) but independent of IKK and IKK (9, 14, 15). Furthermore, under normal conditions, this novel NF-B pathway only occurs in certain cell types at certain stages and responds to very limited stimuli (9), such as lymphotoxin (LT) (9, 16), B-cell activating factor (BAFF) (17, 18), and CD40 ligand (19). These stimuli activate NIK, probably via up-regulation of NIK protein level by de novo protein synthesis and/or stabilization of NIK protein (20, 21). NIK then in turn activates IKK and recruits it into p100 complex via the serine 866 and serine 870 of p100 (22). After recruited into the p100 complex, activated IKK phosphorylates serines 99, 108, 115, 123, and 872 of p100 (22). The phosphorylation of these specific serines results in ubiquitination and subsequent processing of p100 mediated by the -TrCP ubiquitin ligase and 26S proteasome, respectively (9, 20, 22–24).

Although p100 processing is hardly detected in most cell types including T cells, aberrantly persistent processing of p100 has been found in leukemic T cells transformed by the human T cell leukemia virus type I (HTLV-I), in which the processing of p100 is induced by the viral oncoprotein Tax (15). Like NIK, the physiological inducer, Tax also specifically targets IKK to p100, triggering phosphorylation-dependent ubiquitination, and processing of p100 (15, 20, 24). Constitutive processing of p100 has also been found in various lymphomas associated with nfb2 gene rearrangements (15, 25). Interestingly, such genetic alterations always result in generation of C-terminally truncated p100 proteins lacking the processing inhibitory domain (9, 25). Importantly, these C-terminal truncation mutants of p100 show oncogenic ability in vitro, and overexpression of p52 in the absence of p100 in p100 knock-in mice causes marked gastric and lymphocyte hyperplasia and early postnatal death of mice (26, 27). These findings strongly suggest that deregulated processing of p100 contributes to human malignancies, particularly the lymphomas and leukemia (25).

Recent studies suggested that the physiological and pathogenic processing of p100 is regulated by both common and different mechanisms (20). While NIK-mediated p100 processing depends on -TrCP, constitutive processing of p100 is independent of this protein and is regulated by p100 nuclear shuttling (23, 24, 28). On the other hand, Tax-induced processing of p100 involves both mechanisms (20, 24). However, under all these conditions, the processing of p100 is generally regulated by a ternary domain of p100 consisting of both its N- and C-terminal sequences (20). Here, we provide both genetic and biochemical evidence demonstrating that the constitutive processing of p100 also requires IKK but not IKK or IKK, suggesting another common mechanism for p100 processing. However, NIK, the activator of IKK for inducible p100 processing under physiological conditions is not involved in constitutive processing of p100. We also find that IKK and p100 phosphorylation are dispensable for p100 nuclear shuttling. It seems that p100 nuclear expression is not sufficient, though required, for constitutive processing, since the constitutive processing forms of p100 translocate into the nucleus of IKK null cells but defective in processing. Additionally, the phosphorylation-deficient mutants of the p100 constitutive processing forms fail to undergo processing, although they are still expressed in the nucleus.

	MATERIALS AND METHODS

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Expression Vectors and Antibodies—Expression vectors encoding p100 and its C-terminal deletion mutants (p100-(1–665) and p100-(1–454)), IKK, HA-tagged NIK and its C-terminal mutant (NIK-c), have been described before (9, 20, 22). p100-(1–665) S/A and p100-(1–454) S/A constructs, which harbor serine to alanine substitutions at residues 99, 108, 115, and 123, were generated by site-directed mutagenesis as described (22, 24). The p100 mutants HuT-78 and LB-40, C-terminal HA-tagged p100-(1–665) and their S/A constructs were created by routine cloning strategy. The anti-IKK antibody (anti-IKK, H744) was bought from Santa Cruz Biotechnology. The anti-HA monoclonal antibody (anti-HA, 12CA5) was purchased from Roche Applied Science. The fluorescein isothiocyanate (FITC)-conjugated anti-mouse and anti-rabbit secondary antibody as well as Hoechst 33258 were from Amersham Biosciences and Molecular Probes, respectively. The antibodies used recognizing the N (anti-p100N) or C terminus (anti-p100C) of p100 were as described previously (20).

Cell Culture and Transfection—293 cells and murine embryonic fibroblasts (MEFs) derived from wild type, IKK^–/–, IKK^–/–, IKK^–/–, and Aly/Aly mice were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and 2 mM L-glutamine. 293 and MEF cells were transfected with DEAE-dextran and FuGENE 6 reagent (Roche Applied Science), respectively (20, 29–31).

In Vivo p100 Processing Assays—293 or MEF cells were transfected by labeled expression vectors and lysed in radioimmunoprecipitation assay buffer (RIPA buffer) (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1 mM EDTA, 0.25% sodium deoxycholate, 1% Nonidet P-40, 1 mM dithiothreitol, 1 mM phenylmethylsulfony fluoride) supplemented with a protease inhibitor mixture, followed by immunoblotting (IB) using p100N antibody as described previously (9, 14, 15).

Immunofluorescence Assays—MEF cells were transfected with p100, C-terminal HA-tagged p100-(1–665) (p100-(1–665)-HA) or its serine mutant, p100-(1–665) S/A-HA. After 24 h, the recipient cells were directly fixed, permeabilized, and sequentially incubated with anti-p100 C (for p100) or anti-HA (for p100-(1–665)-HA and its S/A mutant), followed by FITC-conjugated anti-rabbit or anti-mouse secondary antibodies. The subcellular localization of stained proteins was detected using an inverted fluorescence microscope. The cells were also counterstained with Hoechst 33258 for nuclear staining by detecting DNA as described previously (20).

	RESULTS

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The IKK Phosphorylation Serines of p100 Are Essential for Its Constitutive Processing—Although we have demonstrated that IKK is required for p100 processing induced by both NIK and Tax (14, 15), its role in the constitutive processing of p100 remains to be investigated. For this study, the N-terminal IKK phosphorylation serines within p100, which play an essential role in inducible processing of p100 (22, 24), were mutated from four constitutive processing forms of p100: LB40, HuT-78, p100-(1–665), and p100-(1–454) (9, 20) (Fig. 1A). Among them, LB40 and HuT-78 proteins are expressed by the rearranged nfb2 gene in B cell chronic lymphocytic leukemia and T cell lymphoma, respectively (32, 33). The constitutive processing of these p100 constructs and their serine-alanine mutants was examined. Consistent with our previous studies (9, 20, 24), these p100 proteins exhibited constitutive processing (Fig. 1B, odd lanes). Importantly, substitutions of the IKK phosphorylation serines with alanines efficiently prevented their constitutive processing (Fig. 1B, even lanes), suggesting a positive role of IKK in constitutive processing of p100.

View larger version (39K): [in this window] [in a new window]   FIG. 1. The IKK phosphorylation serines are required for constitutive processing of p100. A, schematic representation of constitutive forms of p100 and their serine mutants. The full-length p100 is also represented. The abbreviations used are: NPS, N-terminal IKK phosphorylation site; GRR, glycine-rich region; ARD, ankyrin repeat domain; DD, death domain (also named processing inhibitory domain (PID)); WT, wild-type. The arrow indicates the processing site. The number of targeted serine residues is also shown. LB40 and HuT-78 are derived from B cell chronic lymphocytic leukemia and T cell lymphoma, respectively. LB40 is equivalent to p100-(1–702); HuT-78 is a fusion protein containing 1–665 amino acids of p100 at the N terminus and another three heterologous amino acids (serine-alanine-serine) at the C terminus. B, mutation of IKK phosphorylation serines blocks the constitutive processing of LB40, HuT-78, p100-(1–665), and p100-(1–454). 293 cells were transfected with LB40, HuT-78, p100-(1–665), and p100-(1–454) or their serine-to-alanine mutants, followed by IB analysis using anti-p100N to detect protein expression of p100 mutants and their processed product, p52 (p100 processing). The asterisk indicates a nonspecific background band co-migrated with p52.

View larger version (41K): [in this window] [in a new window]   FIG. 2. Constitutive processing of p100 requires IKK. A, IKK and IKK are not required for constitutive processing of p100 C-terminal mutants. MEFs derived from wild-type (WT), IKK–/– and IKK–/– mice were transfected with LB40, HuT-78 or p100-(1–665), followed by in vivo p100 processing assays. The p100 mutants, p52 and endogenous p100, are indicated. B, IKK is important for constitutive processing of p100 C-terminal mutants. IKK–/– MEFs were transfected with LB40, HuT-78, or p100-(1–665) in the absence or presence of IKK, followed by p100 processing assays. The ratio of the processed products, p52, to their precursors, p100 mutants, is indicated in the figure. The expression level of transfected IKK was also examined using an IKK-specific antibody for IB. The nonspecific background band is labeled with an asterisk in lower panel.

View larger version (34K): [in this window] [in a new window]   FIG. 3. NIK is not involved in constitutive processing of p100. A, dominant-negative NIK fails to block the constitutive processing of p100. 293 cells were transfected with indicated constructs, followed by p100 processing assays. The protein expression of NIK and NIK-c was also detected. The expression level of NIK-c in lane 3 is similar to that in lane 5 (date not shown). B, p100 C-terminal mutants undergo constitutive processing in NIK Aly/Aly MEFs. Aly/Aly MEFs were transfected with LB40, HuT-78, or p100-(1–665), followed by p100 processing assays. WT, wild-type.

View larger version (41K): [in this window] [in a new window]   FIG. 4. The nuclear shuttling of p100 is independent of IKK. Wild-type (WT) and IKK–/– MEFs were transfected with p100 or C-terminal HA-tagged p100-(1–665) or p100-(1–665) S/A mutants. The subcellular localization of p100 mutant was detected by immunofluorescence assays using anti-p100C (for p100) or anti-HA (for p100-(1–665) and its S/A mutant) as primary antibodies and FITC-conjugated anti-rabbit or anti-mouse Ig as secondary antibodies (upper panels). The nuclei were counterstained with Hoechst 33258 and visualized with a UV filter (lower panels).

	DISCUSSION

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Although processing of p100 is usually tightly controlled, this proteolytic event could be efficiently activated at least by NIK, Tax, and the loss of the C-terminal portion of p100. While NIK-mediated p100 processing is dependent on the E3 ligase -TrCP, constitutive processing of p100 C-terminal deletion mutants does not require this ligase but rather is regulated by the nuclear shuttling of p100 (23, 24, 28). On the other hand, both -TrCP-dependent and -independent mechanisms contribute to Tax-induced processing of p100 (24). Despite these differences, common mechanisms regulating p100 processing also exist. For example, p100 processing under all these situations is controlled by its cis-acting domain (20). In the current study, we have demonstrated an essential role of IKK in the constitutive processing of p100 using both biochemical and genetic approaches (Figs. 1 and 2). These data clearly indicate another general mechanism for regulation of p100 processing, since IKK is also required for NIK- and Tax-induced p100 processing (14, 15).

It seems that IKK-mediated phosphorylation of p100 is to trigger recruitment of ubiquitin ligase(s) and subsequent ubiquitination of p100 (20, 22, 23, 24). However, the -TrCP ubiquitin ligase, known to be involved in inducible processing of p100, is not required for constitutive processing of p100 (20, 23, 24). These findings suggest that another yet-to-be identified ubiquitin ligase may be involved. In support of this idea, we have shown that IKK is also required for -TrCP-independent ubiquitination and processing of p100 induced by Tax (15, 24). Furthermore, the constitutive processing of p100 requires proteasome (9), although the ubiquitination and processing of the constitutive processing forms of p100 is weak and slow, compared with the inducible ubiquitination and processing of p100 (9, 23, 24). It appears that the unidentified ligase is located in the nucleus, since the -TrCP-independent p100 processing is regulated by p100 nuclear shuttling, and -TrCP-dependent processing only occurs in the cytoplasm (20). Clearly, efforts should be focused on identification of this ligase in the future.

	FOOTNOTES

 
^* This work was supported by Grant 704050 (to G. X.) from the New Jersey State Commission on Cancer Research and by the District #5 Ahepa/Daughters of Penelope Cancer Research Foundation, Inc. (to G. X.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Cell Biology and Neuroscience, Nelson Biological Laboratory, Rutgers, The State University of New Jersey, 604 Allison Rd., Piscataway, NJ 08854. Tel.: 732-445-2839; Fax: 732-445-5870; E-mail: xiao{at}biology.rutgers.edu.

¹ The abbreviations used are: IKK, IB kinase; NIK, NF-B-inducing kinase; -TrCP, -transducin repeat-containing protein; HA, hemagglutinin; IB, immunoblotting; MEF, murine embryonic fibroblast; FITC, fluorescein isothiocyanate.

	ACKNOWLEDGMENTS

 
We thank M. Ernst, D. Green, W. C. Greene, T. Honjo, M. Karin, E. Kieff, N. Rice, and S. C. Sun for expression vectors, antibodies, and MEFs.

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This Article Abstract Full Text (PDF) All Versions of this Article: 280/11/9765    most recent C400502200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qing, G. Articles by Xiao, G. Search for Related Content PubMed PubMed Citation Articles by Qing, G. Articles by Xiao, G. Social Bookmarking                      What's this?