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Molecular and Cellular Biology, January 2003, p. 402-413, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.402-413.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

ßTrCP-Mediated Proteolysis of NF-{kappa}B1 p105 Requires Phosphorylation of p105 Serines 927 and 932

Valerie Lang,1 Julia Janzen,1 Gregory Zvi Fischer,2 Yasmina Soneji,1 Sören Beinke,1 Andres Salmeron,3 Hamish Allen,3 Ronald T. Hay,4 Yinon Ben-Neriah,2 and Steven C. Ley1*

Division of Immune Cell Biology, National Institute for Medical Research, London NW7 1AA,1 School of Biology, University of St. Andrews, St. Andrews KY169TS, United Kingdom,4 Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel 91120,2 Abbott Bioresearch Center, Worcester, Massachusetts 01605-43143

Received 23 September 2002/ Accepted 27 September 2002

NF-{kappa}B1 p105 functions both as a precursor of NF-{kappa}B1 p50 and as a cytoplasmic inhibitor of NF-{kappa}B. Following the stimulation of cells with tumor necrosis factor alpha (TNF-{alpha}), the I{kappa}B kinase (IKK) complex rapidly phosphorylates NF-{kappa}B1 p105 on serine 927 in the PEST region. This phosphorylation is essential for TNF-{alpha} to trigger p105 degradation, which releases the associated Rel/NF-{kappa}B subunits to translocate into the nucleus and regulate target gene transcription. Serine 927 resides in a conserved motif (Asp-Ser927-Gly-Val-Glu-Thr-Ser932) homologous to the IKK target sequence in I{kappa}B{alpha}. In this study, TNF-{alpha}-induced p105 proteolysis was revealed to additionally require the phosphorylation of serine 932. Experiments with IKK1-/- and IKK2-/- double knockout embryonic fibroblasts demonstrate that the IKK complex is essential for TNF-{alpha} to stimulate phosphorylation on p105 serines 927 and 932. Furthermore, purified IKK1 and IKK2 can each phosphorylate a glutathione S-transferase-p105758-967 fusion protein on both regulatory serines in vitro. IKK-mediated p105 phosphorylation generates a binding site for ßTrCP, the receptor subunit of an SCF-type ubiquitin E3 ligase, and depletion of ßTrCP by RNA interference blocks TNF-{alpha}-induced p105 ubiquitination and proteolysis. Phosphopeptide competition experiments indicate that ßTrCP binds p105 more effectively when both serines 927 and 932 are phosphorylated. Interestingly, however, ßTrCP affinity for the IKK-phosphorylated sequence on p105 is substantially lower than that on I{kappa}B{alpha}. Thus, it appears that reduced p105 recruitment of ßTrCP and subsequent ubiquitination may contribute to delayed p105 proteolysis after TNF-{alpha} stimulation relative to that for I{kappa}B{alpha}.

* Corresponding author. Mailing address: Division of Immune Cell Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. Phone: 00-44-8816-2463. Fax: 00-44-8906-4477. E-mail: sley{at}nimr.mrc.ac.uk.

Molecular and Cellular Biology, January 2003, p. 402-413, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.402-413.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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