Striking back at the activator: how IkappaB kinase terminates antigen receptor responses.
Antigen recognition by the T cell receptor (TCR) elicits several intracellular signaling cascades, one of which activates the transcription factor NF-kappaB through IkappaB kinases (IKK). NF-kappaB regulates lymphocyte differentiation, proliferation, and apoptosis; thus, tight temporal control of its activation is required to prevent harmful immune cell dysregulation. Although considerable insight into the IKK and NF-kappaB activation process has emerged, less is known about the temporal regulation and termination of immunoreceptor signaling. Two recent studies have revealed that the scaffold protein Bcl10--which, together with CARMA1 and Malt1, forms the TCR-induced IKK-activating CBM complex--is a negative feedback substrate for IKK. IKKbeta initially contributes to CBM formation--which is required for full IKK activation--and then, through carboxyl-terminal Bcl10 phosphorylation, disrupts this structure to terminate signaling. IKK triggers Bcl10 degradation by the ubiquitin-proteasome system through phosphorylation of Bcl10 at other sites. Thus, inactivation through negative feedback mechanisms is an intrinsic property of the TCR-induced NF-kappaB pathway.
Hinz
Michael
M
Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
Scheidereit
Claus
C
D000818:Animals; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013379:Substrate Specificity
D011948:Receptors, Antigen, T-Cell; D051550:I-kappa B Kinase