Atypical IκB proteins in immune cell differentiation and function

Abstract

The NF-κB/Rel signalling pathway plays a crucial role in numerous biological processes, including innate and adaptive immunity. NF-κB is a family of transcription factors, whose activity is regulated by the inhibitors of NF-κB (IκB). The IκB proteins comprise two distinct groups, the classical (cytoplasmic) and the atypical (nuclear) IκB proteins. Although the cytoplasmic regulation of NF-κB is well characterised, its nuclear regulation mechanisms remain marginally elucidated. However, work from recent years indicated that nuclear IκBs contribute significantly to the modulation of NF-κB-mediated transcription in the immune system. Here, we discuss the role of the atypical IκB proteins Bcl-3, IκBζ, IκBNS, IκBη and IκBL for the regulation of gene expression and effector functions in immune cells.

Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation

“…Although the downstream mechanism of IκBζ function remains unclear, it is suggested that IκBζ recruits epigenetic factors to the promoter region of its target genes, thereby modulating gene expression (13,14). Induction of IκBζ and subsequent target gene expression has been investigated in different cell types, such as keratinocytes, macrophages, dendritic cells, and T cells (15). Stimulation of keratinocytes with IL-17A or IL-36 induces IκBζ expression, leading to the induction of several psoriasis-associated target genes, such as Cxcl8, Cxcl2, Defb4, or S100a9 (7,8).…”

TACI expression and plasma cell differentiation are impaired in the absence of functional IκBNS

“…In classical NF‐κB signaling, the NF‐κB transcription factors are rendered transcriptionally inactive through sequestering in the cytoplasm by inhibitors of κB (IκB), such as IκB‐α, IκB‐β, IκB‐ε, and the p50 precursor p105 . In addition to the cytoplasmic IκB proteins, the atypical nuclear IκB proteins BCL‐3, IκBζ, IκBNS and IκBη were identified based on their ankyrin repeat structure through which they are able to bind NF‐κB proteins and regulate their activity . For example, IκBNS was found to bind nuclear p50, p52, p65, RelB and c‐Rel .…”

“…IκBNS is also required for normal function in other immune cells. In T cells, IκBNS mediates TCR‐induced cell death during negative selection in the thymus, governs the development of regulatory T cells through the induction of Foxp3 and is essential for cytokine production in T H 17 cells . In the myeloid lineage, IκBNS dampens the proinflammatory response through suppression of IL‐6 and IL‐12p40 production in macrophages and regulating IL‐10 production by dendritic cells upon lipopolysaccharide (LPS) stimulation …”

“…14 In addition to the cytoplasmic IjB proteins, the atypical nuclear IjB proteins BCL-3, IjBf, IjBNS and IjBg were identified based on their ankyrin repeat structure through which they are able to bind NF-jB proteins and regulate their activity. 15 For example, IjBNS was found to bind nuclear p50, p52, p65, RelB and c-Rel. 16,17 Rather than being constitutively expressed and regulated through proteasomal degradation similar to classical IjB proteins, expression of IjBNS is induced by BCR ligation or TLR stimulation.…”

“…In T cells, IjBNS mediates TCR-induced cell death during negative selection in the thymus, 16 governs the development of regulatory T cells through the induction of Foxp3 20 and is essential for cytokine production in T H 17 cells. 15 In the myeloid lineage, IjBNS dampens the proinflammatory response through suppression of IL-6 and IL-12p40 production in macrophages and regulating IL-10 production by dendritic cells upon lipopolysaccharide (LPS) stimulation. [26][27][28] In this study, we investigated potential reasons for the lack of TI responses in the absence of IjBNS using the bumble mouse strain.…”