A pervasive role of ubiquitin conjugation in activation and termination of IkappaB kinase pathways

Abstract

The nuclear factor (NF)-kappaB pathway is a paradigm for gene expression control by ubiquitin-mediated protein degradation. In stimulated cells, phosphorylation by the IkappaB kinase (IKK) complex primes NF-kappaB-inhibiting IkappaB molecules for lysine (Lys)-48-linked polyubiquitination and subsequent destruction by the 26S proteasome. However, recent studies indicate that the ubiquitin (Ub) system controls NF-kappaB pathways at many levels. Ub ligases are activated by different upstream signalling pathways, and they function as central regulators of IKK and c-Jun amino-terminal kinase activation. The assembly of Lys 63 polyUb chains provides docking surfaces for the recruitment of IKK-activating complexes, a reaction that is counteracted by deubiquitinating enzymes. Furthermore, Ub conjugation targets upstream signalling mediators as well as nuclear NF-kappaB for post-inductive degradation to limit the duration of signalling.

Figure 1

Components of ubiquitin binding and editing in the IKK/NF-κB pathways in humans. Ubiquitin (Ub) ligases (E3s) are involved in the activation or termination phases of IKK/NF-κB signalling. Catalytic domains are coloured green (non-degradative) or red (degradative). Potential Ub-binding domains for Ub^Lys63 are in light green, and those for degradative polyUb are in purple. Domains with deubiquitinating activity are shown in yellow. BIR, baculoviral inhibition of apoptosis protein repeat; C2, protein kinase C conserved region 2; CAP-Gly, cytoskeleton-associated protein; CARD, caspase recruitment domain; c-IAP1, cellular inhibitor of apoptosis protein; CUE, domain possibly involved in binding to ubiquitin-conjugating enzymes; HECT, homologue of E6-AP carboxyl terminus; Ig, immunoglobulin; MALT1, mucosa-associated lymphoid tissue 1; OTU, ovarian tumour type (cysteine protease); PB1, Phox and Bem1 domain; PLIC, protein linking IAP with cytoskeleton; RING, really interesting new gene; SH2, Src homology 2; SOCS, suppressor of cytokine signalling; STI1, heat-shock chaperonin-binding motif; TAB, TAK1-binding protein; TRABID, TRAF-binding domain; TRAF, TNF-receptor-associated factor domain; βTrCP, transducin-repeat-containing protein; UCH, ubiquitin C-terminal hydrolase; UBA, ubiquitin-associated; UBL, ubiquitin-like; WW, domain with two conserved Trps; ZF, zinc finger; ZF-RBZ, ZF in Ran-binding protein; ZF-ZZ, ZF in dystrophin. Conserved domains were predicted by using http://smart.embl-heidelberg.de.

Figure 2

The ubiquitin system in the activation and termination phases of IKK/NF-κB signalling. (A) Ubiquitin (Ub) ligases (shown in green) catalyse the assembly of Ub^Lys63 chains (green) on TRAF2, TRAF6, RIP and IKK-γ, which is thought to recruit the protein kinase TAK1 through association with TAB2 or TAB3 (light green). TAK1 activates the IKK complex, which subsequently targets IκBs for βTrCP-mediated Ub^Lys48 modification. The ubiquitin-like PLIC may provide a link between the ubiquitination machinery and the proteasome (Kleijnen et al, 2000). (B) In the termination phase, DUBs (shown in yellow) catalyse the disassembly of Ub^Lys63 chains and arrest upstream signalling to IKKs. Distinct E3 Ub ligases (in red) terminate IKK/NF-κB signalling by the addition of Ub (red) to the substrates for subsequent degradation. Colours for Ub-binding and -editing domains are defined in Fig 1. Abbreviations as in Fig 1; BCL10, B-cell lymphoma 10; CARMA1, caspase recruitment domain-containing membrane-associated guanylate kinase protein 1; PKC, protein kinase C; PLC, phospholipase C.