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文献汇报
XX 2019-02-21Βιβλιοθήκη NF-κB pathway
NEMO IKK
无活性
多聚泛素化 无活性
K63-linked polyubiquitin and IKK activation
TRAF6
Ubc13 Uev1A
Ub K63-linked polyubiquitin
Activate K63-linked polyubiquitin
Polyubiquitination of RIP1 is not restricted to K63-linkage
Ubc5 and cIAP1 catalyze polyubiquitination of RIP1
The RING domain ubiquitin ligases TRAF2, cIAP1 and cIAP2 have been implicated in NF-κB activation in the TNF pathway, but whether loss of cIAPs enhances or reduces NF-κB activation has been a subject of debate (Bertrand et al., 2008; Mahoney et al., 2008;Varfolomeev et al., 2008; Vince et al., 2007).
Tetracycline-inducible system to replace endogenous ubiquitin in U2OS
T55-K63/E64-R72 T55-R63/E64-R72 L43-K48/E64-R72
Ubiquitination is required for IKK activation by both IL-1β and TNFα
Ubc5 and cIAP1 catalyze polyubiquitination of RIP1
Summary
IKK activation by IL-1β requires Ubc13 and K63 polyubiquitination. In contrast, IKK activation by TNFα requires Ubc5 and cIAPs but not Ubc13 or K63 polyubiquitination.
IKKγ （NEMO） IKKγ （NEMO）
recruits IKK to the TAK1 complex, facilitating IKK phosphorylation by TAK1 P IKK IKKβ P
TAK1
IKKβ IKKα
Activate
Polyubiquitinated（K63）RIP1 binds to TAB2 and NEMO, thereby recruiting the TAK1 and IKK complexes, respectively, to the membrane receptor complex to facilitate the activation of these kinases.
K63 of ubiquitin is required for IKK activation by IL-1β, but not TNFα
Catalysis by Ubc13 is required for IKK activation by IL-1β, but not TNFα
Ubc5 is required for IKK activation by TNFα
Ubc5 is required for polyubiquitination of RIP1
Ubc5 is required for polyubiquitination of RIP1
Polyubiquitination of RIP1 is not restricted to K63-linkage
Genetic evidence that K63 of ubiquitin is important for IKK activation is still lacking, owing to the technical difficulty of mutating endogenous ubiquitin genes in vivo.
