NF-kappaB Signaling
NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) represent a group of homo- or heterodimeric transcription factors that are central in a network of various signal transduction pathways. A vast array of signals such as cytokines, growth factors and hormones, infections, oxidative stress, certain drugs, and chemical substances are transmitted to the NF-kB complexes and passed on to influence processes ranging from cell survival, apoptosis, and proliferation to immune response and inflammation. They are therefore highly pleiotropic, i.e. they influence a multitude of phenotypic trait.
NF-kB is a homo- or heterodimeric complex formed in mammals by the Rel homology domain (RHD)-containing proteins RelA/p65, RelB, c-Rel, NFKB1/p105/p50, and NFKB2/p100/p52. The heterodimeric RELA/p50 complex of the canonical pathway appears to be the most abundant one. All NF-kB proteins have an N-terminal RHD which plays an essential role in DNA binding, as dimerization interface and for the binding to IkB inhibitors. NF-kB proteins do however differ in their C-terminal: class I proteins RELA, RELB and c-Rel contain are characterized by a trans-activator domain whereas class II proteins NFKB1/p105/p50 and NFKB2/p100/p52 have ankyrin repeat transrepression domain.
In the canonical pathway, NF-kappaB are kept in an inactive state in the cytoplasm through interaction with inhibitory IkB proteins. Upon stimulation of the NF-kB signaling by one of the abovementioned stimuli these regulators are phosphorylated by an IKK kinase complex composed of protein kinases IKK-alpha, IKK-beta, and IKBKG(NEMO). The phosphorylation marks the IkB inhibitors for proteasomal degradation, thus setting NF-kB free. Once freed, NF-kB are further activated by post-translational modification and translocated to the nucleus where it interacts with specific kB elements . Depending on the cell type and nature of the received stimulus the non-canonical pathway can be engaged. The core regulator for this pathway is NF-kB inducing kinase (NIK/MAP3K14) which activates IKK-alpha, thus leading to phosphorylation of p100. p100 is then processed to p52 leading to the activation and nuclear translocation of the p52/RelB NF-kB dimer. The canonical pathway does not depend on protein synthesis and responds rapidly to numerous stimuli for a wide variety of downstream effects. In contrast, the non-canonical pathway is slow and persistent and responds only to a subset of signals for more specific effects.
NF-kappaB Signaling is deeply intertwined with several pathways such as MAPK signaling and the p53 pathway. Addtionally there is significant crosstalk between NF-kB signaling and autophagy, with both pathways sharing common regulatory mechanisms that influence cellular responses such as inflammation, cell survival, and tumor progression. Autophagic activity can regulate NF-kB activation by controlling the degradation of signaling intermediates, while NF-kB itself modulates autophagy-related genes, thereby integrating cellular stress responses. Additionally, NF-kB signaling is tightly linked to the regulation of neuroinflammation, playing a critical role in mediating immune responses within the central nervous system. Furthermore, interactions between NF-kB signaling and gut microbiota have been observed, where bacterial infections influence NF-kB activity and contribute to gastrointestinal inflammatory responses and tumorigenesis. These interconnected regulatory networks underscore the extensive role of NF-kB beyond immune signaling, integrating metabolic, inflammatory, and cellular homeostasis mechanisms.
Related Pathways and Resources
- MAPK Signaling
- P53 Signaling
- Apoptosis
- Autophagy
- Cell-Division Cycle
- Neurodegenerative Diseases
- Hallmarks of Cancer
References:
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