Signal-induced Ubiquitination of IκB Kinase-β

Abstract

Initiation of the genetic programs for inflammation and immunity involves nuclear mobilization of transcription factor NF-κB. This signal-dependent process is controlled in part by the β-catalytic subunit of IκB kinase (IKKβ), which marks IκBα and other cytoplasmic inhibitors of NF-κB for proteolytic destruction. The catalytic activity of IKKβ is stimulated by pathologic and physiologic inducers of NF-κB, such as the Tax oncoprotein and proinflammatory cytokines. We now report evidence that these NF-κB inducers target IKKβ for conjugation to ubiquitin (Ub) in mammalian cells. The apparent molecular size of modified IKKβ is compatible with monoubiquitination rather than attachment of a multimeric Ub chain. The modification is contingent upon signal-induced phosphorylation of the activation T loop in IKKβ at Ser-177/Ser-181. The formation of IKKβ-Ub conjugates is disrupted in cells expressing YopJ, a Ub-like protein protease that interferes with the NF-κB signaling pathway. These findings indicate an important mechanistic link between phosphorylation, ubiquitination, and the biologic action of IKKβ.