Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

IKK (IκB Kinase) Complex

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101969


Historical Background

IKK (B kinase) is the central regulator of the NF-κB signaling pathway, which plays a key role in immunity, inflammation, and cell survival (Karin and Ben-Neriah 2000; Hayden and Ghosh 2012). NF-κB is the generic name of a family of inducible dimeric transcription factors that are sequestered in the cytoplasm of resting cells by interaction with inhibitory protein IκBs. Upon cell stimulation ΙκBs are phosphorylated, and this modification triggers their ubiquitination and destruction by the proteasome. This allows free NF-κB proteins to translocate in the nucleus and to activate their target genes (Fig. 1).
IKK (IκB Kinase) Complex, Fig. 1

The canonical pathway of NF-κB activation. Upon activation by cell membrane-associated or cytoplasmic receptors (R1 to R5) recognizing specific ligands, a process requiring or not TAK1, the IKK complex phosphorylates the inhibitory protein IκB, inducing its degradation. This allows NF-κB dimers to translocate in the nucleus to regulate genes controling a large number of physiological processes

Identification of the kinase specifically responsible for IκB phosphorylation remained a challenge in the NF-κB field for some time before various complementary approaches allowed full definition of its nature and composition. Instrumental in this was first the characterization of the phosphorylated residues of IκBα responsible for its degradation (serine 32 and 36 located in a short conserved motif) (Whiteside and Israël 1997). This allowed the search by cell extracts fractionation of a kinase able to phosphorylate a polypeptidic sequence including them. Using this strategy, Karin’s lab initially identified a protein of 85 kD that appeared to be catalytically active only after stimulation of cells with TNF-α, a classical NF-κB activator (DiDonato et al. 1997). This inducible feature, combined with the specific recognition of Ser32/36 residues, demonstrated that it was indeed a bona fide IκB kinase. Sequence of this kinase proved identical to CHUK, a previously described kinase with no assigned function (Connelly and Marcu 1995). Given its demonstrated participation in NF-κB activation, CHUK was coined as IKkinase α (IKKα). The same group co-purified with IKKα an 87 kD protein presenting high sequence similarity and a catalytic activity against IκBα also (Zandi et al. 1997). It was called IKKβ. At the same time, using a similar purification approach, Mercurio et al. also identified these two kinases and called them IKK1 for the one identical to IKKα and IKK2 for the one identical to IKKβ (Mercurio et al. 1997). Finally, using a yeast two-hybrid screen aimed at identifying interacting partners of NIK, a kinase activating NF-κB through a poorly defined mechanism at that time, Goeddel’s lab also identified CHUK (Régnier et al. 1997). As previously reported by DiDonato et al., this kinase was shown to exhibit activity toward the IκBα polypeptide in an in vitro kinase assay. A search for IKKα homologs through database screening by the same laboratory subsequently identified IKKβ (Woronicz et al. 1997).

Very quickly following their identification, IKKα and IKKβ were shown to form homo- and heterodimers, suggesting that they may act in concert to phosphorylate the two serine residues of IκBα and could represent the catalytic core of a so-called IKB kinase (IKK) complex. A support for the existence of such a protein complex came from gel filtration experiments revealing that IKKα and IKKβ were present in identical species migrating with a molecular weight of 400–600 kD. This suggested that (many?) other components may participate within the same entity in recognition/degradation of IκBα during the NF-κB activation process.

Using an unbiased approach based on the genetic complementation of mutant cells unable to activate NF-κB in response to a large set of stimuli, Yamaoka et al. were the first to identify a non-catalytic component of murine IKK, interacting with more affinity to IKKβ than IKKα. It was called NF-κB essential modulator (NEMO) (Yamaoka et al. 1998). A human protein of the same size (50 kD) and exhibiting a very similar sequence was found in the purified preparation of IKK of DiDonato et al. (see above) and called IKKγ (Rothwarf et al. 1998). Independently, Mercurio et al. used immunoprecipitation of IKK catalytic subunits in HeLa cells to identify associated proteins and found again the human homologue of NEMO that they called IKKAP1 (Mercurio et al. 1999).

Since then, no other components of IKK have been identified as genuine core components of this kinase despite the claim that ELKS (Ducut Sigala et al. 2004) and chaperones Cdc37 and Hsp90 (Chen et al. 2002) may represent additional subunits. As said above, gel filtration analysis initially suggested that many additional subunits might exist. Nevertheless, this view was somehow tempered following the observation that the simple mixing of purified IKKα, IKKβ, and NEMO proteins could produce upon chromatographic analysis a species with a much larger molecular weight than predicted, mostly because of the very elongated structure of NEMO (see below) causing an aberrant delay in gel elution.

Structure and Mechanisms of Activation

IKK is currently viewed as a heterodimer of IKKα/IKKβ associated with a dimer of NEMO. It is not excluded that IKKβ homodimers associated with NEMO also exist.

As said above, IKKα and IKKβ are very close relatives (50% identity and 70% homology) of a small subfamily of kinases also comprising two other IKK-like members, IKKε and TBK1. Their primary sequence analysis combined with functional studies has identified several important domains (Fig. 2a). The first one, located at the N-terminus, is the catalytic domain which contains an active lysine at aa 44 and an activation T-loop with two serine residues as phosphoacceptor sites. At the center of the molecule were identified sequences showing homology to leucine zipper (LZ) and helix-loop-helix (HLH) motifs and participating in IKK dimerization. Finally, at the C-terminus is located a short sequence containing six conserved aa (LDWSWL) recognizing NEMO (NBD, NEMO-binding domain) (May et al. 2000).
IKK (IκB Kinase) Complex, Fig. 2

Structure of the catalytic subunits of IKK. a Functional domains of IKKα and IKKβ. KD kinase domain, ULD ubiquitin-like domain, SDD scaffold/dimerization domain, N NEMO-binding domain, LZ leucine zipper, HLH helix-loop-helix, S phosphoacceptor serine sites. b Structure of the active conformation of IKKβ (The structure is from https://www.ncbi.nlm.gov/Structure/)

The recent crystallization of IKKβ (Xu et al. 2011; Polley et al. 2013) has revealed several additional and sometimes unpredicted features deserving comments. First, the overall structure of the dimer resembles a pair of shears (Fig. 2b) with the dimerization interface (the « blade ») appearing much more complex than initially thought. It consists in an α-helical scaffold/dimerization domain (SDD) formed by a large sequence composed of six α-helices and encompassing the previously described LZ and HLH, which do not exist as such. The SDD adopts an elongated conformation with the α2 and α6 helices (70 aa and 77 aa, respectively) running parallel on each IKK2β promoters and providing the hydrophobic residues that allow dimerization. The “handle” includes the kinase domain (KD), which has a typical bilobal form, and a previously poorly characterized domain, the ubiquitin-like domain (ULD), which by interacting with both the SDD and the KD allows full structuration of the catalytic moiety. This domain was originally identified by May et al. (May et al. 2004) who proposed its participation in substrate recognition.

It has been shown that the IKKβ dimer could adopt either a close or an open conformation, the latter one associated with the active state of the kinase. Such opening of the dimer would result in oligomerization. Then, interaction of oligomers would favor trans-autophosphorylation (Fig. 3) (see below for the various proposed modes of IKK activation).
IKK (IκB Kinase) Complex, Fig. 3

Proposed mechanism of IKK activation. KD kinase domain, ULD ubiquitin-like domain, SDD scaffold/dimerization domain, NBD NEMO-binding domain (Adapted from Polley et al. 2013)

The overal structure of IKKα is very similar to the one of IKKβ, in particular concerning the dimerization interface which also involves a SDD making contacts with an ULD that was originally thought to be present only in IKKβ (Polley et al. 2016). Interestingly, a higher-order organization of IKKα dimers has also been observed in crystals, a hexameric structure formed by a trimer of dimers. This peculiar arrangement is not observed with IKKβ questioning its putative relevance in the autophosphorylation of IKK (IKKα/IKKβ associated with NEMO). Instead it may represent the active species required for RelB/p52 phosphorylation in the noncanonical pathway of NF-κB signaling which only involves IKKα dimers (see below).

NEMO is also composed of several domains (Fig. 4) whose specific functions/structures have been fully elucidated only recently. It consists in a very elongated dimeric protein mostly composed of α-helices. At the N-terminus (aa 44–aa 110) is located a sequence recognizing the NBD of IKKα and IKKβ, associated with a sequence favoring dimerization. The short region located between aa 80 and 110 represents a preferential target for modulating the interaction between IKKα/IKKβ and NEMO and consequently blocking the NF-κB activation process (NBD peptide (May et al. 2000). A long coiled-coil domain is located more centrally. It provides interaction interfaces for NEMO regulators such as LUBAC and viral proteins v-FLIP and Tax. Displaying a similar helical structure is a first ubiquitin-binding domain (NEMO ubiquitin-binding (NUB) domain) located between aa 292 and 322. It has been shown to interact with K63-linked or linear polyubiquitinated chains. Following the NUB domain is a proline-rich region whose function remains unclear but might participate in interaction with CYLD deubiquitinase, a negative regulator of IKK/NF-κB activation. Finally, NEMO contains at the very C-terminal end a zinc finger (ZF). This domain has been shown to also exhibit affinity for polyubiquitin, cooperating with the NUB domain. It may also play an important function in helping IKKα/β to distinguish IκB proteins from other substrates (Schröfelbauer et al. 2012).
IKK (IκB Kinase) Complex, Fig. 4

Structure of NEMO. a Functional domains. Dim dimerization sequence, IKBD IKK-binding domain, HD helical domains, NUB NEMO ubiquitin-binding domain, Pro(n) proline-rich sequence, ZF zinc finger. b Structure of the most important domains with, left to right, the IKK-binding domain (NEMO in cyan and blue, IKKβ in pink and brown) (Rushe et al. 2008), the v-FLIP binding domain in HD2 (Bagnéris et al. 2008), the first ubiquitin-binding domain (NUB) associated with two di-ubiquitins (Rahighi et al. 2009) and the second ubiquitin-binding domain folded as a ZF (Cordier et al. 2009) with its tetra-coordinated Zinc indicated with a white sphere (All the structures are from https://www.ncbi.nlm.gov/Structure/)

Controversy still exists regarding the real affinity of the NUB domain, the ZF, and the full-length NEMO protein toward K-63- versus linear-linked polyubiquitin chains (Rahighi et al. 2009, Laplantine et al. 2009). Further complicating the picture, mixed chains of polyubiquitins have been shown to be produced in cells and could actually represent the genuine target of NEMO. In any case, this intricate mode of ubiquitin recognition represents the heart of NEMO function. Through its interaction with polyubiquitinated partners, NEMO triggers the recruitment of IKK and its catalytic activation either by upstream kinase TAK1, the catalytic component of the TAK complex which is also recruited to ubiquitinated partners by TAB2/TAB3 subunits (see below), or by proximity-induced autophosphorylation (see above).

NEMO posttranslational modifications also regulate its function during the IKK activation process. In addition to being an ubiquitin-binding protein, NEMO is also a target for ubiquitination. Several lysine residues such as Lys285, Lys309, and Lys399 have been shown to be modified by K63- and/or linear-linked chains (Abbott et al. 2004; Tokunaga et al. 2009). This may help strengthening interaction of multiprotein complexes and favor IKK activation. NEMO has also been reported to be phosphorylated at several residues, but the function of these modifications in IKK activity remains less clear. For instance, residue Ser68 can be phosphorylated by IKKα/IKKβ (Palkowitsch et al. 2008), whereas Ser8, Ser17, Ser31, and Ser43 represent targets of GSK-3β (Medunjanin et al. 2016). In both cases this may modulate IKK activity.

Finally, it is worth mentioning that NEMO is often targeted by viral- or bacterial- derived proteins to block the IKK/NF-κB activation process. In several cases, it is degraded by specific proteases, such as members of the 3C-like proteases family (Zhu et al. 2016), and its degradation by the proteasome following K27-linked ubiquitination has also been reported (Ashida et al. 2010).

NF-κB-Related Functions of IKK

As mentioned above IKK is the master regulator of the NF-κB activation process. It is required in every situations in which NF-κB is activated through the so-called canonical pathway. This has been formally demonstrated by studying various cellular systems or by preparing mouse knockouts and further validated through the identification of IKK-related genetic diseases.

Due to space constraints, we will not describe here the many situations in which IKK is required but will provide a short overview of its main physiological functions, only pointing to specific classes of IKK/NF-κB activators. How dysregulation of these functions impact on human health, through the identification of IKK-related genetic diseases, will also be briefly summarized.


A main function of IKK is to allow NF-κB activation when cells are exposed to bacteria- or virus-derived products. In this case, IKK activation is triggered by a collection of receptors belonging to the classes of TLRs, NLRs, or RLRs, which specifically recognize pathogen-associated molecular patterns (PAMPs) such as LPS, flagellin, dsRNA, etc. These receptors, which are present on dendritic cells or macrophages, represent the first line of defense participating in innate immunity (Kaisho et al. 2008). Activated dendritic cells are then able to process and present antigens to T cells, triggering adaptive immunity.

IKK has also various functions at this level. First, it allows activation of NF-κB by the TCR and the BCR. In both cases similar transduction pathways, requiring a members of the CARMA family of protein, CARMA1, and the Bcl10/MALT1 complex connect to IKK (Lin et al. 2004). Moreover, IKK is a key participant in B-cell differentiation and function, leading to synthesis of antibodies (Sasaki et al. 2016). By acting at all these different levels, IKK shapes the immune response. As a consequence, its dysfunction can produce immunodeficiencies or autoimmunity.


IKK is a pivotal player during inflammation (Karin and Greten 2005). On one end, it is activated by a large set of pro-inflammatory cytokines or chemokines, among them TNF-α, IL-1β, οr ΙL-6. On the other, its activation allows synthesis of numerous mediators of the inflammation process, even its own activators. Finally, IKK, more specifically IKKα, controls the resolution of the inflammation. Through this unique property, IKK represents a critical hub in the intricate inflammatory response, and its activation needs to be tightly regulated.

The signaling pathways triggered by TNF-α and IL-1β have been molecularly characterized in great details. In both cases, it has been shown that participants in these signaling pathways, such as RIPK1 or NEMO in the TNF-α pathway and TRAF6 in the IL-1β pathway, are ultimately modified by K63- or linear-linked polyubiquitin chains. These kind of chains do not induce degradation by the proteasome like K48-linked chains but rather allows protein complexes to be formed and activated. In these two examples, ubiquitination of signaling components attracts the TAK complex, through its ubiquitin-binding subunit TAB2/TAB3, and the IKK complex, through its ubiquitin-binding subunit NEMO, allowing activation of IKK (see Fig. 5 for the specific example of TNF-α).
IKK (IκB Kinase) Complex, Fig. 5

Activation of IKK following exposure to TNF-α. Upon recognition of TNF-α by TNF-R1, several proteins are recruited at the intracytoplasmic domain of TNF-R1 and modified by ubiquitination. E3 ligases involved are cIAPs, which synthesize K63-linked chains, and LUBAC, which synthesizes linear-linked chains. These modifications trigger the recruitment of the TAK complex through its subunits TAB2 and TAB3, which exhibit affinity for K63-linked chains, and IKK through its subunit NEMO, which exhibits affinity for both linear- and K63-linked chains. This allows phosphorylation of IKKα/IKKβ by TAK1. Linear ubiquitination of NEMO by LUBAC also favor nucleation of multiprotein complexes. Active IKK then phosphorylates IκBσ, inducing their polyubiquitination by K48-linked chains, a tag for recognition and degradation by the 26S proteasome. Active NF-κB dimers (p50/RelA, the most ubiquitous one presented here) induce the synthesis of proteins neutralizing the proapoptotic complex formed by deubiquitinated RIPK1, caspase 8, and FADD. If activation of NF-κB is inhibited, apoptosis occurs. An alternative mode of cell death (necroptosis) can also be induced if active components of the proapoptotic complex are inhibited. Key components of necroptosis are RIPK3 and MLKL

Cell Death and Proliferation

Deregulation of IKK activity, most often constitutive activation of IKK, is a frequent hallmark of cancer cells. This is due to the role that NF-κB can play in cell proliferation, through activation of cyclin A, D1, or CDK6, for instance, or cell survival, as a brake in TNF-α-induced cell death (Fig. 5). By favoring the establishment and maintenance of an inflammatory environment (see above), NF-κB can also influence tumor growth (Bollrath and Greten 2009).

DNA Damage

IKK activation has been shown to participate in the protection of cells exposed to DNA-damaging agents (McCool and Miyamoto 2012). In this case, the activation mechanism differs greatly from standard activation mechanisms described above. It has been proposed that in the resting situation, a pool of “free” NEMO, whose characteristics remain poorly defined, shuttles between the cytoplasm and the nucleus. Following exposure to DNA-damaging agents, such as etoposide or doxorubicin, free NEMO gets sumoylated and accumulates in the nucleus where it can associate with ATM, the key kinase activated by recognition of double-strand DNA breaks. This induces NEMO phosphorylation by ATM and translocation of both proteins in the cytoplasm where they activate IKK/NF-κB. At this level, a participation of ELKS has been demonstrated (Wu et al. 2010), suggesting that this protein indeed plays a role in IKK activation but in a very specific setting.

IKK-Related Genetic Diseases

Identification of IKK-related inherited diseases has confirmed in humans several previously identified functions of IKK and also revealed new ones (Senegas et al. 2015). As predicted, NEMO and IKBKB mutations generate complex and severe immunodeficiencies. TLR, TCR, and BCR signaling can be impaired leading to attenuated innate and acquired immunity, which results in a broad range of infections caused by bacterial, viral, or parasitic agents. In addition, it has been shown that NEMO deficiency, causing a lack of NF-κB activation, can trigger skin inflammation. Since skin inflammation can also result from excessive NF-κB activity, this demonstrates that skin homeostasis tightly depends on NF-κB signaling. Finally, another important function of IKK/NF-κB in the skin has been revealed through the identification of patients carrying hypomorphic mutation of NEMO. They exhibit impaired development of skin appendages (sweat gland, teeth, hair).

IKKα as a Key Regulator of the Noncanonical Pathway of NF-κB Activation

An alternative pathway of NF-κB activation also exists but only requires IKKα (Sun 2012) (Fig. 6). It is triggered by a limited set of stimuli, such as CD40L or lymphotoxin-β, which trigger synthesis of genes specifically controlled by the NF-κB dimer RelB/p52. In this case, cell stimulation induces stabilization of NIK, a kinase which is highly unstable in resting cells. NIK accumulation allows phosphorylation and activation of IKKα dimers. Active IKKα dimers then phosphorylate p100, a member of the NF-κB family of protein, which is associated in the cytoplasm with another member of this family, RelB. As a result, phosphorylation of p100 triggers its ubiquitination by K48-linked chains and its recognition by the proteasome. In contrast to IκB recognition by the proteasome, which induces full proteolysis, p100 is processed to generate the shorter protein p52. This allows translocation of RelB/p52 in the nucleus where it can regulate the expression of specific target genes controlling B-cell development, dendritic cell maturation, or osteoclastogenesis.
IKK (IκB Kinase) Complex, Fig. 6

The noncanonical pathway of NF-kB activation (See text for details)

Other Functions of IKK and Its Individual Subunits

This review describes the structure and function of the IKK complex, which is primarily involved in NF-κB activation through the canonical pathway. Nevertheless, as a whole the IKK complex can also fulfill few NF-κB-independent functions and the same applies to its individual components.

In two situations that may actually be linked, it has been proposed that IKK regulates processes that do not involve NF-κB. First, it has been shown that IKK regulates the autophagy process upon various forms of cellular stress such as nutrient deprivation, inhibition of mTOR, or endoplasmic reticulum stress (Criollo et al. 2010). Independently, it has been shown that IKK is involved in the response of cells to glutamine removal (Reid et al. 2016). In this specific case, it phosphorylates PFKFB3, inducing its destabilization. Since PFKFB3 is a key component in aerobic glycosis, this contributes to downregulating this metabolic process.

Individually, IKKβ can induce the phosphorylation of a collection of substrates that are not linked to NF-κB signaling (Chariot 2009). NEMO has also a scaffold function during the activation of TBK1/IKKε, two IKK-like enzymes controlling IRF3/IRF7, the kinases that mediate the synthesis of type 1 interferon proteins during viral infection (Zhao et al. 2007). Finally, IKKα have a specific function in the nucleus as an H3 kinase (Sun 2012) and plays a key role in epidermis development during embryogenesis by controlling periderm formation (Richardson et al. 2014).


In most biological processes involving NF-κB, which are many, a participation of IKK has been firmly demonstrated. This indicates the key function of this kinase complex in channeling the effect of a wide range of stimuli to allow the proper coordinated synthesis of many proteins. The core structure of IKK appears quite simple, with two catalytic subunits (IKKα and IKKβ) associated with a single regulatory one (NEMO). As such, this provides an attractive target to efficiently inhibit the NF-κB signaling pathway. Nevertheless, this broad involvement of IKK also precludes acting on NF-κB in a given setting without affecting other of its essential functions. Therefore, the jury is still out regarding the true value of directly targeting IKK for therapeutic purposes. To solve this uncertainty, several specific fields of research should be investigated more thoroughly. Among them are the exact catalytic relationship that exists between IKKα and IKKβ, with the two enzymes working in concert within IKK despite exhibiting a quite different level of activity. This may provide a way to act distinctly on NF-κB-controlled signaling pathways. Moreover, the characterization of NEMO posttranslational modifications (ubiquitination, phosphorylation, etc.) remains a neglected field that may provide strategies to target IKK context specifically.



I thank Dr. Jérémie Gautheron for preparing Fig. 5.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.INSERM U1038/BGE/BIG, CEA GrenobleGrenobleFrance