The p105 NF-ĸB precursor is a pseudo substrate of the ubiquitin ligase FBXO7, and its binding to the ligase stabilizes it and results in stimulated cell proliferation

The NF-κB transcription factor is involved in inflammation and cell proliferation, survival, and transformation. It is a heterodimer made of p50 or p52 and a member of the Rel family of proteins. p50 and p52 are derived from limited ubiquitin- and proteasome-mediated proteolytic processing of the larger precursors p105 and p100, respectively. Both precursors can be either processed or completely degraded by the ubiquitin-proteasome system. Previous work in our laboratory identified KPC1 as a ubiquitin ligase that mediates processing of p105 to the p50 subunit. Overexpression of the ligase leads to increased level of p50 with a resultant marked tumor-suppressive effect. In the present study, we identify FBXO7, a known ubiquitin ligase that binds to p105 and ubiquitinates it, but surprisingly, leads to its accumulation and to that of p65 - the Rel partner of p50 - and to increased cell proliferation. Importantly, a ΔF-Box mutant of FBXO7 which is inactive has similar effects on accumulation of p105 and cell proliferation, strongly suggesting that p105 is a pseudo substrate of FBXO7. •FBXO7 and FBXO7ΔF-Box bind to p105, but only wild-type FBXO7 ubiquitinates p105.•Both FBXO7 and FBXO7ΔF-Box increase the level of p105 and p65.•Both FBXO7 and FBXO7ΔF-Box slow the degradation of p105.•Both FBXO7 and FBXO7ΔF-Box stimulate p105-dependent cell proliferation.•The findings suggest that p105 is a pseudo substrate of FBXO7.