Figure 2.

Canonical and non-canonical NF-κB signaling in T cells. Left. This cartoon illustrates the membrane receptors involved in delivering canonical NF-κB signaling in T cells, including the T Cell Receptor (TCR) and members of the TNF receptor superfamily. TCR stimulation leads to the recruitment of the kinase ZAP70 to the phosphorylated ITAMs of the CD3 chains within the TCR/CD3 complex. This recruitment enables ZAP70 to phosphorylate LAT and SLP76, forming the LAT/SLP76 signalosome, which subsequently recruits the guanine exchange factor Vav and the kinase GLK. These components contribute to the membrane translocation and activation of PKCθ. Next, PKCθ phosphorylates CARMA1, resulting in the formation of the CBM complex (comprised of CARMA1, BCL10, and MALT1). The subsequent recruitment of the ligase TRAF6 and the kinase TAK1 into the NF-κB signalosome leads to the ubiquitination of NEMO and the phosphorylation of IKKα and IKKβ. The active IKK complex (NEMO-IKKα-IKKβ) phosphorylates IκBα, which retains NF-κB heterodimers (p50-RelA or p50-c-Rel) in the cytosol, targeting IκBα for degradation. This process allows free NF-κB dimers to translocate to the nucleus and drive gene expression. TNF receptor signaling converges with TCR signaling at the level of TAK1 and the IKK complex; however, each receptor leads to the assembly of specific signalosomes where TRAF proteins play critical roles. Right. Non-canonical NF-κB signaling differs from canonical signaling in terms of the NF-κB dimers (p52-RelB), the IKK complex (which consists of a dimer of IKKα), the kinase activity (NIK), and the membrane receptors depicted in this cartoon. Additionally, while not included in the figure, evidence exists for crosstalk between both pathways. This figure was created using BioRender.com.