The IKK complex, a central regulator of NF-kappaB activation

Abstract

The IKK kinase complex is the core element of the NF-kappaB cascade. It is essentially made of two kinases (IKKalpha and IKKbeta) and a regulatory subunit, NEMO/IKKgamma. Additional components may exist, transiently or permanently, but their characterization is still unsure. In addition, it has been shown that two separate NF-kappaB pathways exist, depending on the activating signal and the cell type, the canonical (depending on IKKbeta and NEMO) and the noncanonical pathway (depending solely on IKKalpha). The main question, which is still only partially answered, is to understand how an NF-kappaB activating signal leads to the activation of the kinase subunits, allowing them to phosphorylate their targets and eventually induce nuclear translocation of the NF-kappaB dimers. I will review here the genetic, biochemical, and structural data accumulated during the last 10 yr regarding the function of the three IKK subunits.

Figure 1.

The kinase subunits. The domains of the two kinase subunits are indicated: The kinase domain is located at the amino-terminus (the activation loop is also shown: Amino acids 176–180 of IKKα and 177–181 of IKKβ). An ubiquitin-like domain (aa 307–384 in IKKβ) is located carboxy-terminal to the kinase domain of IKKβ (but not IKKα), and seems to be involved in the catalytic activity of IKKβ. The function of the leucine zipper domain is to allow homo- or heterodimerization of the kinases. The role of the helix loop helix domain is less clear, but it seems to be involved in the modulation of the kinase activity. Finally a ∼40 amino-acid region at the extreme carboxyl terminus of the kinases (aa 705–743) is required for their interaction with NEMO.

Figure 2.

The NEMO molecule. Human NEMO is a 419–amino-acid dimeric molecule essentially structured under the form of a series of parallel intermolecular coiled coils (based on the available structural data). CC1, coiled coil 1; CC2, coiled coil 2; NOA, ubiquitin binding domain; ZF, Zinc Finger (and a second ubiquitin binding domain). The determination of the structure of linker 1 indicated that it is also structured as an intermolecular coiled coil. The structure of CC1 and linker II has not been determined yet. It must be stressed that the dimeric structure of NEMO is relatively unstable in the absence of interacting partners (kinases, polyubiquitin, …). The region of interaction with some of these partners has been indicated: The amino terminus is involved in the interaction with the two kinases. Linker 1 is involved in the interaction with viral transactivators such as HTLV1 Tax and KSHV v-FLIP. The entire carboxy-terminal region is required for transmission of the signal, and the NOA and the ZF domains bind polyubiquitin chains.

Figure 3.

The NF-κB response to TNF. TNF induces trimerization of the TNF receptor, leading to the recruitment of TRADD, the E3 ubiquitin-ligase TRAF2 (and/or TRAF5), and the kinase RIP1 (other recruited molecules have been omitted for simplicity). K63-linked polyubiquitination of RIP1 on Lys 377, possibly mediated by TRAF2/5 (curved arrow), leads to the recruitment of the TAK1/TAB1/TAB2 complex through the ubiquitin-binding zinc finger of TAB2 (TAB2 can be replaced by TAB3, and TAB1 has been omitted for clarity). Through an unknown mechanism, this leads to the activation of the TAK1 kinase. The IKK complex is also recruited to these K63 polyubiquitin chains through the ubiquitin-binding domain of NEMO, allowing TAK1 to phosphorylate and activate the IKKs. K63-linked polyubiquitination of NEMO has been observed, but its actual role is currently unclear. One possibility is that it allows recruitment of the TAK1 complex in close proximity to the IKK kinase subunits, allowing their activation by TAK1; alternatively it might allow NEMO oligomerization through cross-recognition by its own ubiquitin binding domain. Whatever the exact mechanism of activation of the IKKs, they eventually phosphorylate the IκBα inhibitory subunit of NF-κB. IκBα is then polyubiquitinated through Lys48-linked polyubiquitin chains by the β-TrCP E3 ubiquitin ligase, leading to its degradation by the proteasome and to nuclear translocation of free NF-κB dimers, ultimately ending in activation of NF-κB target genes.