Positive and Negative Regulation of IκB Kinase Activity Through IKKβ Subunit Phosphorylation

TLDR

IKK phosphorylates IkappaB proteins, triggering NF‑κB activation, and is composed of the catalytic subunits IKKα and IKKβ plus the regulatory subunit IKKγ. Activated IKKβ autophosphorylates a carboxyl‑terminal serine cluster. Phosphorylation of two activation‑loop sites on IKKβ is required for TNF and IL‑1–mediated activation, whereas analogous sites on IKKα are dispensable, showing that IKKβ—not IKKα—is the target of pro‑inflammatory stimuli, and this phosphorylation subsequently down‑regulates IKK activity to curb prolonged inflammation.

Abstract

IkappaB [inhibitor of nuclear factor kappaB (NF-kappaB)] kinase (IKK) phosphorylates IkappaB inhibitory proteins, causing their degradation and activation of transcription factor NF-kappaB, a master activator of inflammatory responses. IKK is composed of three subunits-IKKalpha and IKKbeta, which are highly similar protein kinases, and IKKgamma, a regulatory subunit. In mammalian cells, phosphorylation of two sites at the activation loop of IKKbeta was essential for activation of IKK by tumor necrosis factor and interleukin-1. Elimination of equivalent sites in IKKalpha, however, did not interfere with IKK activation. Thus, IKKbeta, not IKKalpha, is the target for proinflammatory stimuli. Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.