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NF‐κB p105 is a target of IκB kinases and controls signal induction of Bcl‐3–p50 complexes
Author(s) -
Heissmeyer Vigo,
Krappmann Daniel,
Wulczyn F.Gregory,
Scheidereit Claus
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.17.4766
Subject(s) - phosphorylation , biology , p50 , kinase , microbiology and biotechnology , iκb kinase , activator (genetics) , transcription factor , repressor , ubiquitin , proteasome , protein serine threonine kinases , signal transduction , nf κb , biochemistry , protein kinase a , receptor , gene
The NF‐κB precursor p105 has dual functions: cytoplasmic retention of attached NF‐κB proteins and generation of p50 by processing. It is poorly understood whether these activities of p105 are responsive to signalling processes that are known to activate NF‐κB p50–p65. We propose a model that p105 is inducibly degraded, and that its degradation liberates sequestered NF‐κB subunits, including its processing product p50. p50 homodimers are specifically bound by the transcription activator Bcl‐3. We show that TNFα, IL‐1β or phorbolester (PMA) trigger rapid formation of Bcl‐3–p50 complexes with the same kinetics as activation of p50–p65 complexes. TNF‐α‐induced Bcl‐3–p50 formation requires proteasome activity, but is independent of p50–p65 released from IκBα, indicating a pathway that involves p105 proteolysis. The IκB kinases IKKα and IKKβ physically interact with p105 and inducibly phosphorylate three C‐terminal serines. p105 is degraded upon TNF‐α stimulation, but only when the IKK phospho‐acceptor sites are intact. Furthermore, a p105 mutant, lacking the IKK phosphorylation sites, acts as a super‐repressor of IKK‐induced NF‐κB transcriptional activity. Thus, the known NF‐κB stimuli not only cause nuclear accumulation of p50–p65 heterodimers but also of Bcl‐3–p50 and perhaps further transcription activator complexes which are formed upon IKK‐mediated p105 degradation.