Regulation of B-cell function by NF-kappaB c-Rel in health and disease

Abstract

B cells mediate humoral immune response and contribute to the regulation of cellular immune response. Members of the Nuclear Factor kappaB (NF-κB) family of transcription factors play a major role in regulating B-cell functions. NF-κB subunit c-Rel is predominantly expressed in lymphocytes, and in B cells, it is required for survival, proliferation, and antibody production. Dysregulation of c-Rel expression and activation alters B-cell homeostasis and is associated with B-cell lymphomas and autoimmune pathologies. Based on its essential roles, c-Rel may serve as a potential prognostic and therapeutic target. This review summarizes the current understanding of the multifaceted role of c-Rel in B cells and B-cell diseases.

Keywords: Antibody production; Autoimmunity; B lymphocytes; Lymphoma; Transcription.

Fig. 1

Schematic representation of c-Rel domains and posttranslational modification sites. The principal structural domains of c-Rel protein are shown, which include N-terminal Rel homology domain (RHD), nuclear localization sequence (NLS), Rel inhibitory domain (RID), and two transactivation domains (TAD). Amino acid positions of c-Rel domains and posttranslational modification sites such as ubiquitination, phosphorylation (P), and O-GlcNAcylation (O-G) complied from corresponding information for chicken, mouse, and human c-Rel are indicated in the figure. Blue dotted lines represent the position of amino acid sequence encoded by exon 9

Fig. 2

Signaling pathways and cellular processes regulated by c-Rel in B cells. Upon activation of BCR, CD40, TLR, and BAFF-R by their by cognate ligands, c-Rel/NF-κB complexes translocate into the nucleus, bind κB sites in the DNA, and control the expression of various genes. Alterations in the gene expression, in turn, regulate an array of cellular processes in B cells, as shown in the figure. Abbreviations used in the figure are as follows: BCR B-cell receptor, TLR Toll-like receptor, BAFF-R B-cell activating factor receptor, E2F3a E2F transcriptional factor 3a, CDK cyclin-dependent Kinase, pRB retinoblastoma protein, IRF4 Interferon regulatory factor 4, NF-κB2 Nuclear Factor kappaB 2, NOS2 nitric oxide synthase, Bcl2 B-cell CLL/Lymphoma 2 antiapoptotic protein, Bim Bcl2 homology 3-only protein, Bcl-xL B-cell lymphoma-extra-large, EZH2 Enhancer of zeste homolog 2. Question mark (?) indicates that the role of indicated gene/protein in c-Rel-mediated regulation of cellular process in B-cell is not yet certain