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Post-Translational Modifications Regulating the Activity and Function of the Nuclear Factor Kappa B Pathway

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Post-Translational Modifications Regulating the Activity and Function of the Nuclear Factor Kappa B Pathway Oncogene (2006) 25, 6717–6730 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc REVIEW Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway ND Perkins Division of Gene Regulation and Expression, University of Dundee, Dundee, Scotland, UK The diverse cellular and biological functions of the nuclear activation. Nevertheless, regardless of the stimulus, all factor kappa B (NF-jB) pathway, together with the pathways leading to NF-kB activation rely on inducing catastrophic consequences of its aberrant regulation, numerous post-translational modifications of either the demand specific and highly regulated control of its IKKs, the IkBs or the NF-kB subunits themselves. Since activity. As described in this review, regulation of the induction of NF-kB involves its regulated nuclear NF-jB pathway is brought about through multiple post- localization, there are many critical cytoplasmic mod- translational modifications that control the activity of the ifications required to either inactivate the IkB inhibitory core components of NF-jB signaling: the IjB kinase proteins or to activate the NF-kB subunits directly. Of (IKK) complex, the IjB proteins and the NF-jB subunits possibly equal importance, the function of NF-kB themselves. These regulatory modifications, which include complexes is also controlled by many nuclear modifica- phosphorylation, ubiquitination, acetylation, sumoylation tions, which can regulate transcriptional activity, DNA and nitrosylation, can vary, depending on the nature of the binding and target gene specificity. In addition, the tight NF-jB-inducing stimulus. Moreover, they frequently have temporal control of NF-kB activity means that path- distinct, sometimes antagonistic, functional consequences ways exist to limit its time in the nucleus and post- and the same modification can have different effects translational modifications of the subunits can also depending on the context. Given the important role of contribute to the termination of the NF-kB response. NF-jB in human health and disease, understanding these This review discusses these modifications and how they pathways will not only provide valuable insights into contribute to each step of the NF-kB pathway. mechanism and function, but could also lead to new drug targets and the development of diagnostic and prognostic biomarkers for many pathological conditions. Activation of the IKK complex Oncogene (2006) 25, 6717–6730. doi:10.1038/sj.onc.1209937 Keywords: NF-kB; IKK; IkB; phosphorylation; Induction of nuclear NF-kB activity by many stimuli, ubiquitination; modification particularly those involved in the immune and inflam- matory responses as well as some genotoxic agents and cellular stresses, requires the activation of the IKK complex (Hayden and Ghosh, 2004; Perkins and Gilmore, 2006). Although many upstream signaling pathways lead to IKK activation, there are a number of Introduction common features associated with stimulation of IKK catalytic activity. The activity of nuclear factor kappa B (NF-kB) proteins is regulated by hundreds of different stimuli in all cell types, with many functional consequences (Pahl, 1999; Ubiquitination of NEMO Perkins and Gilmore, 2006). The general framework of The first step in IKK activation involves modification of the canonical and noncanonical pathways leading to the regulatory subunit of the IKK complex, NF-kB activation of NF-kB via degradation of IkB and nuclear essential modifier (NEMO, also known as IKKg), through translocation of NF-kB has been reviewed elsewhere K63-linked polyubiquitination (Burns and Martinon, (Hayden and Ghosh, 2004; Gilmore, 2006). While 2004; Chen, 2005; Krappmann and Scheidereit, common themes exist for induction of NF-kB, for 2005) (Figure 1; Table 1). In contrast to K48-linked example, many inducers of NF-kB work through ubiquitination, K63 linkages do not lead to proteasomal induction of the IkB kinase (IKK) complex, there are degradation, but in this case function as a binding site also numerous exceptions and alternative pathways of for other signaling molecules required for activation of the IKK catalytic subunit IKKb (Burns and Martinon, 2004; Chen, 2005; Krappmann and Scheidereit, 2005). Correspondence: Dr ND Perkins, Division of Gene Regulation and Expression, School of Life Sciences, MSI/WTB Complex, University There are multiple NEMO ubiquitin E3 ligases, which of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK. vary depending upon the activating pathway (Burns E-mail: [email protected] and Martinon, 2004; Chen, 2005; Krappmann and Post-translational modifications of the NF-jB pathway ND Perkins 6718 Figure 1 Post-translational modifications and structure of the IKK subunits. Shown are schematic diagrams of the principal structural motifs of NEMO, IKKa and IKKb in relation to the known post-translational modifications that regulate their activity. It is possible that IKKa may undergo similar modifications to those seen in IKKb, but these have not yet been described in the literature. Phosphorylations at the C-terminus of IKKb are indicated as being approximately 10, since the exact number were not definitively established by the original mutagenesis studies (Delhase et al., 1999). Numbering is from the human proteins, although some definitions of where a domain begins and ends might differ between publications. Abbreviations: CC1 and CC2, coiled coil regions 1 and 2; LZ, leucine zipper motif; ZF, zinc-finger domain; HLH, helix-loop-helix domain; NBD, NEMO-binding domain. The code for the different modifications is shown in the figure. Table 1 Post-translational modifications of the IKK subunits Site(s) Modification Enzyme(s) Effect Reference NEMO (IKKg) S31, S43 and S376 Phosphorylation IKKb Unclear Prajapati and Gaynor (2002), Carter et al. (2003) S85 Phosphorylation ATM Activation Wu et al. (2006b) K277 and K309 Sumoylation and Not known Activation Huang et al. (2003a) ubiquitination (mono) K285 Ubiquitination NOD2/RIP2 Activation Abbott et al. (2004) (K63 linked) K399 Ubiquitination Bcl10/Malt/TRAF6 Activation Sun et al. (2004), Zhou et al. (2004) (K63 linked) aa397-417 Ubiquitination Not known Activation Tang et al. (2003) (K6 linked) IKKb S177 and S181 Phosphorylation TAK1 and others Activation Wang et al. (2001) Y188 and Y199 Phosphorylation c-Src dependent Activation Huang et al. (2003b) Approx. 10 S (aa Phosphorylation IKKb Inhibition Delhase et al. (1999) 664–756) K173 Ubiquitination Not known Activation Carter et al. (2005) (mono) C179 S-Nitrosylation N/A Inhibition Reynaert et al. (2004) IKKa T23 Phosphorylation Akt/PKB Activation Ozes et al. (1999) S176 and S180 Phosphorylation NIK Activation Ling et al. (1998), Senftleben et al. (2001) Oncogene Post-translational modifications of the NF-jB pathway ND Perkins 6719 Scheidereit, 2005). In turn, these different E3 ligases can has also been reported to lead to mono-ubiquitination cause ubiquitination of different lysine residues in of IKKb at Lys-163 (Carter et al., 2005). Mutation of NEMO. For example, T-cell receptor (TCR) activation Lys-163 impairs subsequent IKKb auto-phosphoryla- results in Bcl10/MALT1-mediated, TNF receptor-asso- tion of further C-terminal serine residues in cells ciated factor 6 (TRAF6)-dependent, K63 ubiquitination (Delhase et al., 1999; Schomer Miller et al., 2006), but of NEMO at Lys-399 (Sun et al., 2004; Zhou et al., 2004). not in vitro (Carter et al., 2005). TRAF6, as well as other family members such as TRAF2 An alternative pathway leading to IKKb activation and 5, also mediate NEMO polyubiquitination in loop phosphorylation has also been described: this response to tumor necrosis factor a (TNF) and inter- pathway involves the c-Src-dependent phosphorylation leukin-1 (IL-1) receptor signaling. By contrast, bacterial of Tyr-188 and Tyr-199 of IKKb in response to infection can result in nucleotide binding oligomerization TNF and 12-O-tetradecanoylphorbol-13-acetate (TPA) domain 2 (NOD2, also known as CARD15) and receptor stimulation (Huang et al., 2003b). Given the diversity of interacting protein 2 (RIP2)-dependent K63-linked poly- NF-kB signaling pathways, it is possible that other ubiquitination of NEMO at lysine 285 (Abbott et al., phosphorylation events also lead to IKKb activation. 2004). TNF signaling has also been reported to result in IKKb has also been reported to be a target of the inhibitor of apoptosis protein 1 (c-IAP1)-dependent, constitutive S-nitrosylation at Cys-179, a site within the K6-linked ubiquitination of NEMO within its zinc-finger activation loop (Reynaert et al., 2004). This modifica- region (Tang et al., 2003). tion inhibits IKKb activity, and TNF stimulation results in denitrosylation at Cys-179 (Reynaert et al., 2004). Whether this denitrosylation of Cys-179 is directly IKK subunit modification linked to active site phosphorylation is not known. NEMO ubiquitination is just one component in a Interestingly, this same cysteine residue is also required complex series of ubiquitin-based modifications of the for some natural product-mediated inhibition of IKKb signaling molecules involved in IKK complex activation (Liang et al., 2006b). (Burns and Martinon, 2004; Chen, 2005; Krappmann A further regulatory event post-IKKb activation has and Scheidereit, 2005). These include K63-linked auto- also been reported. This involves the IKKb-mediated ubiquitination of TRAF2 and TRAF6, as well as phosphorylation of NEMO at Ser-31, Ser-43 and K63-linked polyubiquitination of the RIP1 kinase. Ser-376,
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