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Shared pathways of IkappaB kinase-induced SCF betaTrCP-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and I kappa B alpha

Item Type:Article
Title:Shared pathways of IkappaB kinase-induced SCF betaTrCP-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and I kappa B alpha
Creators Name:Heissmeyer, V. and Krappmann, D. and Hatada, E.N. and Scheidereit, C.
Abstract:p105 (NFKB1) acts in a dual way as a cytoplasmic IκB molecule and as the source of the NF-κB p50 subunit upon processing. p105 can form various heterodimers with other NF-κB subunits, including its own processing product, p50, and these complexes are signal responsive. Signaling through the IκB kinase (IKK) complex invokes p105 degradation and p50 homodimer formation, involving p105 phosphorylation at a C-terminal destruction box. We show here that IKK{beta} phosphorylation of pl05 is direct and does not require kinases downstream of IKK. p105 contains an IKK docking site located in a death domain, which is separate from the substrate site. The substrate residues were identified as serines 923 and 927, the latter of which was previously assumed to be a threonine. S927 is part of a conserved DSGψ motif and is functionally most critical. The region containing both serines is homologous to the N-terminal destruction box of IκB{}alpha, -{beta}, and -ε. Upon phosphorylation by IKK, p105 attracts the SCF E3 ubiquitin ligase substrate recognition molecules βTrCP1 and βTrCP2, resulting in polyubiquitination and complete degradation by the proteasome. However, processing of p105 is independent of IKK signaling. In line with this and as a physiologically relevant model, lipopolysaccharide (LPS) induced degradation of endogenous p105 and p50 homodimer formation, but not processing in pre-B cells. In mutant pre-B cells lacking IKKγ, processing was unaffected, but LPS-induced p105 degradation was abolished. Thus, a functional endogenous IKK complex is required for signal-induced p105 degradation but not for processing.
Keywords:Amino Acid Motifs, Amino Acid Sequence, Binding Sites, Cell Line, Conserved Sequence, DNA-Binding Proteins, I-kappa B Kinase, I-kappa B Proteins, Lipopolysaccharides, Molecular Sequence Data, Mutation, NF-kappa B, NF-kappa B p50 Subunit, Peptide Synthases, Phosphor Processingylation, Post-Translational Protein, Protein Precursors, Protein-Serine-Threonine Kinases, Recombinant Proteins, SKP Cullin F-Box Protein Ligases, Ubiquitins, Animals
Source:Molecular and Cellular Biology
Publisher:American Society for Microbiology
Page Range:1024-1035
Date:1 January 2001
Official Publication:https://doi.org/10.1128/MCB.21.4.1024-1035.2001
PubMed:View item in PubMed

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