SCFbeta-TrCP ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase

Open Access
Publisher Website
Google Scholar
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 SCFβ‐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 , SCFβ‐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.