Identification of the receptor component of the IκBα–ubiquitin ligase

Avraham Yaron, Ada Hatzubai, Matti Davis, Iris Lavon, Sharon Amit, Anthony M. Manning, Jens S. Andersen, Matthias Mann, Frank Mercurio and Yinon Ben-Neriah ()
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Avraham Yaron: The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School
Ada Hatzubai: The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School
Matti Davis: The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School
Iris Lavon: The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School
Sharon Amit: The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School
Anthony M. Manning: Signal Pharmaceuticals Inc.
Jens S. Andersen: Protana A/S
Matthias Mann: Protana A/S
Frank Mercurio: Signal Pharmaceuticals Inc.
Yinon Ben-Neriah: The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School

Nature, 1998, vol. 396, issue 6711, 590-594

Abstract: Abstract NF-κB, a ubiquitous, inducible transcription factor involved in immune, inflammatory, stress and developmental processes, is retained in a latent form in the cytoplasm of non-stimulated cells by inhibitory molecules, IκBs1,2,3. Its activation is a paradigm for a signal-transduction cascade that integrates an inducible kinase and the ubiquitin–proteasome system to eliminate inhibitory regulators. Here we isolate the pIκBα–ubiquitin ligase (pIκBα-E3) that attaches ubiquitin, a small protein which marks other proteins for degradation by the proteasome system, to the phosphorylated NF-κB inhibitor pIκBα. Taking advantage of its high affinity to pIκBα, we isolate this ligase from HeLa cells by single-step immunoaffinity purification. Using nanoelectrospray mass spectrometry, we identify the specific component of the ligase that recognizes the pIκBα degradation motif as an F-box/WD-domainprotein belonging to a recently distinguished family of β-TrCP/Slimb proteins. This component, which we denote E3RSIκB (pIκBα-E3 receptor subunit), binds specifically to pIκBα and promotes its in vitro ubiquitination in the presence of two other ubiquitin-system enzymes, E1 and UBC5C, one of many known E2 enzymes. An F-box-deletion mutant of E3RSIκB, which tightly binds pIκBα but does not support its ubiquitination, acts in vivo as a dominant-negative molecule, inhibiting the degradation of pIκBα and consequently NF-κB activation. E3RSIκB represents a family of receptor proteins that are core components of a class of ubiquitin ligases. When these receptor components recognize their specific ligand, which is a conserved, phosphorylation-based sequence motif, they target regulatory proteins containing this motif for proteasomal degradation.

Date: 1998
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DOI: 10.1038/25159

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