Counter-regulation in the IKK family.
O'NEILL, LUKE ANTHONY JOHN
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Citation:O'Neill LA, Counter-regulation in the IKK family., The Biochemical Journal, 434, 1, 2011, e1-2
The human IKK [I?B (inhibitor of NF-?B) kinase] family has four members; they are the central kinases of innate immunity. Two members, IKK? and IKK?, the so-called canonical members, phosphoryate I?B?, leading to activation of the transcription factor NF-?B (nuclear factor ?B), which controls the expression of many immune and inflammatory genes. The IKK-related proteins TBK-1 (TANK-binding kinase 1) and IKK? have a different substrate--IRF3 (interferon regulatory factor 3)--which regulates a different set of genes, the products of which include Type I interferons. Toll-like receptors (TLRs) such as the lipopolysaccharide receptor TLR4 or the poly(I:C) receptor TLR3 activate each of the IKKs, but the pro-inflammatory cytokine IL-1 (interleukin 1), which signals in a broadly similar way to the TLRs, has so far been shown to activate only the canonical IKKs. In this issue of the Biochemical Journal, Clark et al. bring new insights into the regulation of IKKs. They demonstrate that IL-1 is in fact able to activate IKK?/TBK-1, which occurs via IKK?/IKK?. The consequence of this is not IRF3 activation, but a negative feedback effect on IKK?/IKK?. This provides us with yet another regulatory feedback loop in a system already replete with control mechanisms. It attests yet again to the importance of keeping these innate immune pathways in check, since if they proceed uncontrolled, inflammatory diseases can occur. Importantly, this study utilized new and specific inhibitors of these kinases, suggesting that the interpretation of any effects the compound might have in vivo may be complex, since for example the inhibition of IKK?/TBK-1 might actually have a pro-inflammatory effect.
Series/Report no:The Biochemical Journal;