Atypical I kappa B proteins - nuclear modulators of NF-kappa B signaling

作者：Schuster Marc; Annemann Michaela; Plaza Sirvent Carlos; Schmitz Ingo^*

来源：Cell Communication and Signaling, 2013, 11: 23.

DOI：10.1186/1478-811X-11-23

• NF-kappaB
• Atypical IkappaB proteins
• BCL-3
• IkappaBNS
• IkappaBzeta
• IkappaBL
• Nuclear NF-kappaB modulation
• IkappaB eta
• MAIL
• NFkBID

Nuclear factor kappa B (NF-kappa B) controls a multitude of physiological processes such as cell differentiation, cytokine expression, survival and proliferation. Since NF-kappa B 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-kappa B signaling, the I kappa B proteins. Classical I kappa Bs, like the prototypical protein I kappa Ba, sequester NF-kappa B transcription factors in the cytoplasm by masking of their nuclear localization signals (NLS). Thus, binding of NF-kappa B to the DNA is inhibited. The accessibility of the NLS is controlled via the degradation of I kappa Ba. 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-kappa B activation. Once their NLS is accessible, NF-kappa B 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 I kappa B proteins, referred to as the BCL-3 subfamily. Those atypical I kappa Bs show entirely different sub-cellular localizations, activation kinetics and an unexpected functional diversity. First of all, their interaction with NF-kappa B transcription factors takes place in the nucleus in contrast to classical I kappa Bs, whose binding to NF-kappa B predominantly occurs in the cytoplasm. Secondly, atypical I kappa Bs are strongly induced after NF-kappa B activation, for example by LPS and IL-1 beta 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 I kappa Bs with DNA-associated NF-kappa B transcription factors can further enhance or diminish their transcriptional activity. Thus, they do not exclusively act as inhibitors of NF-kappa B activity. The capacity to modulate NF-kappa B transcription either positively or negatively, represents their most important and unique mechanistic difference to classical I kappa Bs. Several reports revealed the importance of atypical I kappa B 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 I kappa B functioning.

• 出版日期2013-4-11