SCF(β-TrCP) ubiquitin ligase-mediated processing of NF-κB p105 requires phosphorylation of its C-terminus by IκB kinase

Amir Orian, Hedva Gonen, Beatrice Bercovich, Ifat Fajerman, Esther Eytan, Alain Israël, Frank Mercurio, Kazuhiro Iwai, Alan L. Schwartz, Aaron Ciechanover

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

Abstract

Processing of the p105 precursor to form the active subunit p50 of the NF-κB transcription factor is a unique case in which the ubiquitin system is involved in limited processing rather than in complete destruction of the target substrate. A glycine-rich region along with a downstream acidic domain have been demonstrated to be essential for processing. Here we demonstrate that following IκB kinase (IκK)-mediated phosphorylation, the C-terminal domain of p105 (residues 918-934) serves as a recognition motif for the SCF(β-TrCP) ubiquitin ligase. Expression of IκKβ dramatically increases processing of wild-type p105, but not of p105-Δ918-934. Dominant-negative β-TrCP inhibits IκK-dependent processing. Furthermore, the ligase and wild-type p105 but not p105-Δ918-934 associate physically following phosphorylation. In vitro, SCF(β-TrCP) specifically conjugates and promotes processing of phosphorylated p105. Importantly, the TrCP recognition motif in p105 is different from that described for IκBs, β-catenin and human immunodeficiency virus type 1 Vpu. Since p105-Δ918-934 is also conjugated and processed, it appears that p105 can be recognized under different physiological conditions by two different ligases, targeting two distinct recognition motifs.

Original languageEnglish
Pages (from-to)2580-2591
Number of pages12
JournalEMBO Journal
Volume19
Issue number11
StatePublished - Jun 1 2000

Keywords

  • IκB kinase (IκK)
  • NF-κB
  • P105
  • Ubiquitin
  • β-TrCP

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