Atypical IκB proteins - nuclear modulators of NF-κB signaling.

Nuclear factor κB (NF-κB) controls a multitude of physiological processes such as cell differentiation, cytokine expression, survival and proliferation. Since NF-κB governs embryogenesis, tissue homeostasis and the functions of innate and adaptive immune cells it represents one of the most important and versatile signaling networks known. Its activity is regulated via the inhibitors of NF-κB signaling, the IκB proteins. Classical IκBs, like the prototypical protein IκBα, sequester NF-κB transcription factors in the cytoplasm by masking of their nuclear localization signals (NLS). Thus, binding of NF-κB to the DNA is inhibited. The accessibility of the NLS is controlled via the degradation of IκBα. Phosphorylation of the conserved serine residues 32 and 36 leads to polyubiquitination and subsequent proteasomal degradation. This process marks the central event of canonical NF-κB activation. Once their NLS is accessible, NF-κB transcription factors translocate into the nucleus, bind to the DNA and regulate the transcription of their respective target genes. Several studies described a distinct group of atypical IκB proteins, referred to as the BCL-3 subfamily. Those atypical IκBs show entirely different sub-cellular localizations, activation kinetics and an unexpected functional diversity. First of all, their interaction with NF-κB transcription factors takes place in the nucleus in contrast to classical IκBs, whose binding to NF-κB predominantly occurs in the cytoplasm. Secondly, atypical IκBs are strongly induced after NF-κB activation, for example by LPS and IL-1β stimulation or triggering of B cell and T cell antigen receptors, but are not degraded in the first place like their conventional relatives. Finally, the interaction of atypical IκBs with DNA-associated NF-κB transcription factors can further enhance or diminish their transcriptional activity. Thus, they do not exclusively act as inhibitors of NF-κB activity. The capacity to modulate NF-κB transcription either positively or negatively, represents their most important and unique mechanistic difference to classical IκBs. Several reports revealed the importance of atypical IκB proteins for immune homeostasis and the severe consequences following their loss of function. This review summarizes insights into the physiological processes regulated by this protein class and the relevance of atypical IκB functioning

Atypical IκB proteins in immune cell differentiation and function.

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

IκB(NS) Protein Mediates Regulatory T Cell Development via Induction of the Foxp3 Transcription Factor.

Forkhead box P3 positive (Foxp3(+)) regulatory T (Treg) cells suppress immune responses and regulate peripheral tolerance. Here we show that the atypical inhibitor of NFκB (IκB) IκB(NS) drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, IκB(NS) deficiency leads to a substantial reduction of Foxp3(+) Treg cells in vivo and impaired Foxp3 induction upon transforming growth factor-β (TGF-β) treatment in vitro. Moreover, fewer Foxp3(+) Treg cells developed from IκB(NS)-deficient CD25(-)CD4(+) T cells adoptively transferred into immunodeficient recipients. Importantly, IκB(NS) was required for the transition of immature GITR(+)CD25(+)Foxp3(-) thymic Treg cell precursors into Foxp3(+) cells. In contrast to mice lacking c-Rel or Carma1, IκB(NS)-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IκB(NS) critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IκB(NS) could modulate the Treg cell compartment