[Human pathologies associated with NF-kappaB defects]

NF-kappaB is the generic name of a family of transcription factors which play a critical role in the immune, inflammatory and anti-apoptotic responses. Homo- or heterodimers between the five members of the family are retained in the cytoplasm by inhibitory molecules of the IkappaB family, which mask their nuclear localization signal. Three of these inhibitory molecules have been described: IkappaBalpha, IkappaBbeta and IkappaBepsilon. Following cellular stimulation, IkappaB proteins become phosphorylated by the IkappaB kinase (IKK) complex, ubiquitinated and finally degraded by the proteasome. NF-kappaB is then released and translocated to the nucleus, where it activates its target genes by binding to specific sites in their regulatory regions. The IKK complex is constituted of at least three subunits: two kinases, IKKalpha and IKKbeta, and one regulatory subunit (NEMO/IKKgamma), and it constitutes an integrator of most if not all signals which activate NF-kappaB. Although the mechanisms leading to the degradation of the IkappaB proteins are relatively well understood, the precise molecular mechanisms which result in the activation of the high-molecular-weight kinase complex remain to be elucidated. The central role of the IKK complex is consistent with its involvement in a series of human pathologies. We describe here four pathologies: two are due to mutations in the gene encoding the NEMO molecule, a third one in the gene encoding the IkappaBalpha inhibitor, while the fourth one is due to mutations in a gene which had been described as a tumor suppressor. This gene encodes a protein which interacts with NEMO and exhibits deubiquitinase activity, therefore strengthening the recent hypothesis of the role of non-degradation-linked ubiquitination in NF-kappaB activation.