An unexpected twist to the activation of IKK beta: TAK1 primes IKK beta for activation by autophosphorylation

作者：Zhang Jiazhen; Clark Kristopher; Lawrence Toby; Peggie Mark W; Cohen Philip^*

来源：Biochemical Journal, 2014, 461(3): 531-537.

DOI：10.1042/BJ20140444

• inhibitor of nuclear factor kappa B kinase (IKK)
• interleukin-1 (IL-1)
• linear ubiquitin chain assembly complex (LUBAC)
• nuclear factor kappa B (NF-kappa B)
• transforming growth factor beta-activated kinase-1 (TAK1)

IKK beta {I kappa B [inhibitor of NF-kappa B (nuclear factor kappa B)] kinase beta} is required to activate the transcription factor NF-kappa B, but how IKK beta itself is activated in vivo is still unclear. It was found to require phosphorylation by one or more 'upstream' protein kinases in some reports, but by autophosphorylation in others. In the present study, we resolve this controversy by demonstrating that the activation of IKK beta induced by IL-1 (interleukin-1) or TNF (tumour necrosis factor) in embryonic fibroblasts, or by ligands that activate Toll-like receptors in macrophages, requires two distinct phosphorylation events: first, the TAK1 [TGF beta (transforming growth factor beta)-activated ldnase-1]-catalysed phosphorylation of Ser(177) and, secondly, the IKK beta-catalysed autophosphorylation of Ser(181). The phosphorylation of Ser(177) by TAK1 is a priming event required for the subsequent autophosphorylation of Ser(181), which enables IKK beta to phosphorylate exogenous substrates. We also provide genetic evidence which indicates that the IL-1-stimulated, LUBAC (linear ubiquitin chain assembly complex)-catalysed formation of linear ubiquitin chains and their interaction with the NEMO (NF-kappa B essential modulator) component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKK beta at Ser(177) and IKK alpha at Ser(176). These findings may be of general significance for the activation of other protein kinases.

• 出版日期2014-8-1