RelB: an outlier in leukocyte biology

Abstract

RelB is one of the more unusual members of the NF-κB family. This family, arguably the best known group of transcription regulators, regulates an astonishing array of cell types and biological processes. This includes regulation of cell growth, differentiation and death by apoptosis, and the development and function of the innate and adaptive-immune system. RelB is best known for its roles in lymphoid development, DC biology, and noncanonical signaling. Within the last few years, however, surprising functions of RelB have emerged. The N-terminal leucine zipper motif of RelB, a motif unique among the NF-κB family, may associate with more diverse DNA sequences than other NF-κB members. RelB is capable of direct binding to the AhR that supports the xenobiotic-detoxifying pathway. RelB can regulate the circadian rhythm by directly binding to the BMAL partner of CLOCK. Finally, RelB also couples with bioenergy NAD(+) sensor SIRT1 to integrate acute inflammation with changes in metabolism and mitochondrial bioenergetics. In this review, we will explore these unique aspects of RelB, specifically with regard to its role in immunity.

Keywords: NF-κB; bioenergy; endotoxin tolerance; inflammation.

Figure 1.. Two-dimensional structure of NF-κB family members.

LZ, leucine zipper region; RHR, Rel homology region; TAD, transcription-activating domain; ANK, ankyrin repeat.

Figure 2.. Schematic of the canonical and noncanonical NF-κB pathway.

Canonical signaling causes activation of IKKβ, which degrades (X) IκBα, releasing RelA-p50 heterodimers and allowing them to bind NF-κB sites. Among the genes up-regulated by this are RelB and p100. Canonical signaling also releases RelB-p50 heterodimers; however, these dimers are limited by p100. Noncanonical signaling degrades TRAF3, stabilizing NIK. IKKα is then activated, causing the phosphorylation of p100 and triggering its proteosomal processing into p52. The structure of RelB allows for binding to more diverse sites, as indicated by *NF-kB*.

Figure 3.. Overview of emerging fields of RelB biology.

RelB interacts with factors or complexes in blue. The green processes are those in which RelB is involved, whereas red represents the ultimate responses that RelB regulates.