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. 2025 Apr 30;16:1559494. doi: 10.3389/fimmu.2025.1559494

Figure 1.

Figure 1

The NF-κB signaling network. (A) NF-κB subunits or Rel Homology domain proteins of the NF-κB family. RHD or Rel homology domain determines dimerization with other members of the NF-κB/Rel protein family; NLS or nuclear localization sequence, which also comprises the site for inhibitory interactions with IkB. TAD, or transactivation domain. LZ or leuzin zipper. AnkR or ankyrin repeats domain. DD or death domain. Regulatory phosphorylation sites are denoted by their position in green. Ubiquitination sites (ub) are also shown. (B) Inhibitors of the NF-κB family. The ankyrin repeats in these proteins mediate the binding to NF-κB dimers. The N terminal part of the IκB proteins contain two Ser residues that when phosphorylated allow for quick ubiquitination and degradation of the protein. This is true for the typical IκB proteins but not for the atypical (IκBNS, IκBζ, IkBη and BCL3). The C-terminal regions of p105 and p100 aside from the ankyrin repeats, they also have a death domain. These regions function as IκB for their RHD domain by forming large complexes with Rel proteins. The death domain can undergo cotranslational processing by the 26S proteosome to produce p50 or p52. DD domains also can allow binding to other proteins with complimentary DD domains enabling the assembly of signaling complexes involved in cell death pathways. Some IκB members also have a PEST domain rich in Proline, glutamic acid, serine and threonine. The PEST domain acts as a signal for rapid degradation. (C) The cartoon illustrates the regulation of the IKK complex by the positive actions of signaling intermediates downstream of the T Cell Receptor (TCR) and the TNF receptor. When the TCR binds to antigen presented in the context of MHC, it leads to the phosphorylation of tyrosines in the CD3 chains of the TCR/CD3 complex, facilitating the recruitment of the kinase ZAP-70. ZAP-70 then phosphorylates its substrates, LAT and SLP76, forming the LAT/SLP76 signalosome. Once phosphorylated, this complex enables the recruitment of Vav, which mediates cytoskeleton reorganization and translocation of PKCθ to the membrane. At the membrane, PKCθ phosphorylates CARMA1, leading to the formation of the CBM complex (CARMA1, BCL10, and MALT1). This complex then oligomerizes and recruits the ligase TRAF6 and the kinase TAK1. A dimer of IKKγ (NEMO) binds to IKKα and IKKβ to form the IKK complex. The linear and K63 polyubiquitination of NEMO allows for the activation of the IKK complex, further supported by phosphorylation by TAK1. IKK activation leads to the phosphorylation of the NF-κB subunit p65 and the inhibitory protein IκBα. K63, K11, and M1 ubiquitination represent key processes in NF-κB signaling that enable the formation of non-degradative ubiquitin chains, which are critical for the recruitment of various components of the NF-κB signaling cascade. (D) Downstream of the TNF receptor, TRAF complexes recruit RIPK1. The LUBAC complex catalyzes the M1 polyubiquitination of NEMO which allows for activation of the IKKc. Negative regulation at the level of the IKKc signalosome can occur through various mechanisms, including dephosphorylation and deubiquitination by phosphatases such as PP2A and PP2C, or by deubiquitinases like A20 and CYLD (K63 polyubiquitin chains), and Otulin (M1 polyubiquitin chains). This figure has been created with BioRender.com.