9e6w
NF-kappaB RelA homo-dimer bound to a kappaB site of Cxcl2 gene
Structural highlights
FunctionTF65_MOUSE 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 p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression (By similarity). The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1.[1] [2] Publication Abstract from PubMedNon-consensus binding sites of transcription factors are often observed within the regulatory elements of genes; however, their effect on transcriptional strength is unclear. Within the promoters and enhancers of NF-kappaB-responsive genes, we identified clusters of non-consensus kappaB DNA sites, many exhibiting low affinity for NF-kappaB in vitro. Deletion of these sites demonstrated their collective critical role in transcription. We explored how these "weak" kappaB sites exert their influence, especially given the typically low nuclear concentrations of NF-kappaB. Using proteomics approaches, we identified additional nuclear factors, including other DNA-binding TFs, that could interact with kappaB site-bound NF-kappaB RelA. ChIP-seq and RNA-seq analyses suggest that these accessory TFs, referred to as the TF-cofactors of NF-kappaB, facilitate dynamic recruitment of NF-kappaB to the clustered weak kappaB sites. Overall, the occupancy of NF-kappaB at promoters and enhancers appears to be defined by a collective contribution from all kappaB sites, both weak and strong, in association with specific cofactors. This congregation of multiple factors within dynamic transcriptional complexes is likely a common feature of transcriptional programs. SIGNIFICANCE: The NF-kappaB RelA dimers undergo rapid activation by cytokines and pathogens, driving expeditious expression of target genes upon binding to DNA elements known as kappaB sites, located in the regulatory regions. We find that promoter and enhancer regions of RelA target genes harbor multiple kappaB sites, most being non-consensus with minimal affinity to NF-kappaB in vitro. Recruitment of RelA dimer in vivo depend on these kappaB sites, weak and strong, and appears to be regulated by various accessory factors, including other DNA-binding transcription factors. Overall, this study points to a coordinated network of factors communicating with both weak and strong kappaB sites to recruit RelA dimers, enabling rapid gene activation. Cooperativity among clustered kappaB sites within promoters and enhancers dictates transcriptional specificity of NF-kappaB RelA along with specific cofactors.,Shahabi S, Biswas T, Shen Y, Sanahmadi R, Zou Y, Ghosh G bioRxiv [Preprint]. 2025 Jun 18:2024.07.03.601930. doi: , 10.1101/2024.07.03.601930. PMID:39411157[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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