RELA gene

The RELA gene (RELA stands for "V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A") is a protein-coding gene located on chromosome 11q13.1. Four transcript variants encoding different isoforms have been found for this gene.

NF-kappa-B is a ubiquitous transcription factor that is involved in several biological processes. It is kept in an inactive state in the cytoplasm by specific inhibitors. After degradation of the inhibitor, NF-kappa-B migrates into the cell nucleus and activates the transcription of certain genes. NF-kappa-B consists of NFKB1 or NFKB2, which are bound to either REL, RELA or RELB. The most abundant form of NF-kappa-B is NFKB1, which complexes with the product of this gene, RELA.

Diseases associated with RELA include:

• Autoinflammatory disease, familial, Behcet's-like 3

and

• RELA haploinsufficiency syndrome

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 triggered by a variety 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 consisting of the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The heterodimeric RELA-NFKB1 complex appears to be the most common. The dimers bind to kappa B sites in the DNA of their target genes, and the individual dimers have different preferences for different kappa B sites, which they can bind with different affinity and specificity. Different dimer combinations act as transcriptional activators or repressors.

For example, the heterodimeric NF-kappa-B complexes RELA-NFKB1 and RELA-REL act as transcriptional activators. 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 maintained in an inactive state in the cytoplasm and are complexed with members of the NF-kappa-B inhibitor family (I-kappa-B). In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to various activators and subsequently degraded, releasing the active NF-kappa-B complex, which translocates to the nucleus. The inhibitory effect of I-kappa-B on NF-kappa-B by remaining in the cytoplasm is primarily exerted through its interaction with RELA. RELA has a weak DNA binding site that may contribute directly to DNA binding in the NF-kappa-B complex (Bettelli E et al. 2005). In addition to its activity as a direct transcriptional activator, it is also able to modulate the accessibility of promoters for transcription factors and thereby indirectly regulate gene expression. Associated with chromatin in the NF-kappa B promoter region through association with DDX1. Essential for cytokine gene expression in T cells (Yin X et al. 2021). The homodimeric NF-kappa-B complex RELA-RELA appears to be involved in invasin-mediated activation of IL-8 expression. Important transcription factor that regulates the IFN response during SARS-CoV-2 infection.

1. Badran YR et al. (2017) Human RELA haploinsufficiency results in autosomaldominant chronic mucocutaneous ulceration. J Exp Med 214:1937-1947
2. Bettelli E et al. (2005) Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci U S A 102:5138-43.
3. Comrie WA et al. (2018) RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias. J Allergy Clin Immunol 141:1507-1510.
4. Uhlig HH (2013) Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut 62:1795-805
5. Yin X et al. (2021) MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells. Cell Rep 34:108628.