NFkB Pathway

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.

NFkB Pathway related proteins

NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105.

Apoptotic processIEA:UniProtKB-KW
Cellular response to angiotensinManual Assertion Based On ExperimentIMP:BHF-UCL
Cellular response to dsRNAIEA:Ensembl
Cellular response to interleukin-1Manual Assertion Based On ExperimentIEP:BHF-UCL
Cellular response to interleukin-6Manual Assertion Based On ExperimentIMP:BHF-UCL
Cellular response to lipopolysaccharideManual Assertion Based On ExperimentIMP:MGI
Cellular response to mechanical stimulusManual Assertion Based On ExperimentIEP:UniProtKB
Cellular response to nicotineManual Assertion Based On ExperimentIMP:BHF-UCL
Cellular response to tumor necrosis factorIEA:Ensembl
Cellular response to virusIEA:Ensembl
Inflammatory responseManual Assertion Based On ExperimentTAS:UniProtKB
JNK cascadeIEA:Ensembl
Negative regulation of apoptotic processManual Assertion Based On ExperimentTAS:UniProtKB
Negative regulation of calcidiol 1-monooxygenase activityManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of cellular protein metabolic process1 PublicationIC:BHF-UCL
Negative regulation of cholesterol transport1 PublicationIC:BHF-UCL
Negative regulation of gene expressionManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of inflammatory responseIEA:Ensembl
Negative regulation of interleukin-12 productionIEA:Ensembl
Negative regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of vitamin D biosynthetic process1 PublicationIC:BHF-UCL
Positive regulation of canonical Wnt signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of hyaluronan biosynthetic processManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of lipid storage1 PublicationIC:BHF-UCL
Positive regulation of macrophage derived foam cell differentiation1 PublicationIC:BHF-UCL
Positive regulation of miRNA metabolic processManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:ARUK-UCL
Positive regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIBA:GO_Central
Response to muscle stretchIEA:Ensembl
Transcription by RNA polymerase IIManual Assertion Based On ExperimentTAS:UniProtKB

Nucleus
Cytoplasm
Nuclear, but also found in the cytoplasm in an inactive form complexed to an inhibitor (I-kappa-B).

Immunodeficiency, common variable, 12, with autoimmunity (CVID12):
A primary immunodeficiency characterized by hypogammaglobulinemia and recurrent bacterial infections. About half of patients develop autoimmune features, including cytopenia, as well as generalized inflammation and lymphoproliferation manifest as lymphadenopathy or hepatosplenomegaly.

While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p50 making it an acceptable substrate for the proteasome. This process is known as cotranslational processing. The processed form is active and the unprocessed form acts as an inhibitor (I kappa B-like), being able to form cytosolic complexes with NF-kappa B, trapping it in the cytoplasm. Complete folding of the region downstream of the GRR repeat precludes processing.
Phosphorylation at 'Ser-903' and 'Ser-907' primes p105 for proteolytic processing in response to TNF-alpha stimulation. Phosphorylation at 'Ser-927' and 'Ser-932' are required for BTRC/BTRCP-mediated proteolysis.
Polyubiquitination seems to allow p105 processing.
S-nitrosylation of Cys-61 affects DNA binding.
The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation.