Proteomic screen reveals Fbw7 as a modulator of the NF-κB pathway

Azadeh Arabi, Karim Ullah, Rui M M Branca, Johan Johansson, Daniel Bandarra, Moritz Haneklaus, Jing Fu, Ingrid Ariës, Peter Nilsson, Monique L Den Boer, Katja Pokrovskaja, Dan Grandér, Gutian Xiao, Sonia Rocha, Janne Lehtiö, Olle Sangfelt

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

Fbw7 is a ubiquitin-ligase that targets several oncoproteins for proteolysis, but the full range of Fbw7 substrates is not known. Here we show that by performing quantitative proteomics combined with degron motif searches, we effectively screened for a more complete set of Fbw7 targets. We identify 89 putative Fbw7 substrates, including several disease-associated proteins. The transcription factor NF-κB2 (p100/p52) is one of the candidate Fbw7 substrates. We show that Fbw7 interacts with p100 via a conserved degron and that it promotes degradation of p100 in a GSK3β phosphorylation-dependent manner. Fbw7 inactivation increases p100 levels, which in the presence of NF-κB pathway stimuli, leads to increased p52 levels and activity. Accordingly, the apoptotic threshold can be increased by loss of Fbw7 in a p100-dependent manner. In conclusion, Fbw7-mediated destruction of p100 is a regulatory component restricting the response to NF-κB2 pathway stimulation.

Originele taal-2Engels
Pagina's (van-tot)976
TijdschriftNature communications
Volume3
DOI's
StatusGepubliceerd - 2012
Extern gepubliceerdJa

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