Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation

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