NFκB is the general name for a member of a family of homoand heterodimeric transcription factors made up of the Rel family of proteins. The most common NFκB activated in lymphocytes is a heterodimer of p50:p65Rel.
DAG recruits PKC-˜to the membrane where it phosphorylates CARMA1 Phosphorylated CARMA1 creates a scaffold with BCL10 and MALT1 TRAF-6 is recruited and makes a polyubiquitin scaffold on itself and on NEMO TAK1, recruited by TAB1/2, phosphorylates IKK-°, which phosphorylates I˛B, inducing I˛B ubiquitination and degradation Degradation of I˛B releases NF˛B, which activates transcription in the nucleus PKC-˜CARMA1I°BdegradedI°B˛˝ ˙(NEMO)IKKTAB1/2TAK1ubiquitinBCL10MALT1TRAF-6NF°B
Fig. 7.21 Activation of the transcription factor NFκB by antigen receptors is mediated by protein kinase C. diacylglycerol (daG), produced as a result of T-cell receptor signaling activating pLc-γ, recruits a protein kinase c (pKc-θ) to the membrane, where it phosphorylates a scaffold protein called caRma1. This forms a complex with BcL10 and maLT1 that recruits the e3 ubiquitin ligase TRaf-6. as described in fig. 3.13, the kinase TaK1 is recruited by the polyubiquitin scaffold produced by TRaf-6 and phosphorylates the iκB kinase (iKK) complex [iKKα:iKKβ:iKKγ (nemo)]. iKK phosphorylates iκB, stimulating its ubiquitination, which targets iκB for degradation by the proteasome. This releases nfκB to enter the nucleus and stimulate transcription of its target genes. a defect in nemo that prevents nfκB activation causes immunodeficiency that results in susceptibility to extracellular bacterial infections, along with a skin disease known as ectodermal dysplasia.
The dimer is held in an inactive state in the cytoplasm by binding to an inhibitory protein called inhibitor of κB (IκB). As described for TLR signaling (see Fig. 3.13), TRAF-6 stimulates the degradation of IκB by first activating the kinase TAK1, which activates a complex of serine kinases, IκB kinase (IKK). IKK phosphorylates IκB, causing its ubiquitination and subsequent degradation, and the consequent release and entry into the nucleus of active NFκB. Inherited deficiency of the IKKγ subunit (also called NEMO) leads to a syndrome known as X-linked hypohidrotic ectodermal dysplasia and immunodeficiency, which is characterized by developmental defects in ectodermal structures such as skin and teeth, as well as immunodeficiency.
PKC-θ can also activate JNK, and might be able to activate the transcription factor AP-1 by this route. However, T cells lacking PKC-θ have a defect in AP-1 activation in addition to their defect in NFκB activation, but no defect in JNK activation, indicating that our understanding of this pathway is still incomplete.
7-17 PI 3-kinase activation upregulates cellular metabolic pathways via the serine/threonine kinase Akt.