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Ubiquitin binding mediates the NF-κB inhibitory potential of ABIN proteins

Oncogene volume 27, pages 3739–3745 (2008)Cite this article

Abstract

Deregulated nuclear factor κB (NF-κB) activation plays an important role in inflammation and tumorigenesis. ABIN proteins have been characterized as negative regulators of NF-κB signaling. However, their mechanism of NF-κB inhibition remained unclear. With the help of a yeast two-hybrid screen, we identified ABIN proteins as novel ubiquitin-interacting proteins. The minimal ubiquitin-binding domain (UBD) corresponds to the ABIN homology domain 2 (AHD2) and is highly conserved in ABIN-1, ABIN-2 and ABIN-3. Moreover, this region is also present in NF-κB essential modulator/IκB kinase γ (NEMO/IKKγ) and the NEMO-like protein optineurin, and is therefore termed UBD in ABIN proteins and NEMO (UBAN). Nuclear magnetic resonance studies of the UBAN domain identify it as a novel type of UBD, with the binding surface on ubiquitin being significantly different from the binding surface of other UBDs. ABIN-1 specifically binds ubiquitinated NEMO via a bipartite interaction involving its UBAN and NEMO-binding domain. Mutations in the UBAN domain led to a loss of ubiquitin binding and impaired the NF-κB inhibitory potential of ABINs. Taken together, these data illustrate an important role for ubiquitin binding in the negative regulation of NF-κB signaling by ABINs and identify UBAN as a novel UBD.

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Acknowledgements

We thank B Coornaert and K Heyninck for helpful discussions. This work was supported by grants from the ‘Interuniversitaire Attractiepolen’ (IAP6/18), the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO; Grant 3G010505), and the Geconcerteerde Onderzoeksacties of the Ghent University (GOA; Grant 01G06B6) to RB and from the Deutsche Forschungsgemeinschaft and the German–Israeli Foundation to ID.

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Author notes

  1. S Wagner, I Carpentier and V Rogov: These authors contributed equally to this study

  2. I Dikic and R Beyaert: These authors share senior authorship

Authors and Affiliations

  1. Institute for Biochemistry II, Goethe University Medical School, Frankfurt, Germany

    S Wagner, F Ikeda & I Dikic

  2. Department of Molecular Biology, Ghent University, Zwijnaarde, Belgium

    I Carpentier, M Kreike & R Beyaert

  3. Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Zwijnaarde, Belgium

    I Carpentier, M Kreike & R Beyaert

  4. Institute for Biophysical Chemistry, Goethe University, Frankfurt, Germany

    V Rogov, F Löhr & V Dötsch

  5. Institute of Protein Research, Puschino, Russia

    V Rogov

  6. Laboratory of Immune Cell Biology, National Cancer Institute, NIH, Bethesda, MD, USA

    C-J Wu & J D Ashwell

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  1. S Wagner
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  2. I Carpentier
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Correspondence to I Dikic or R Beyaert.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Wagner, S., Carpentier, I., Rogov, V. et al. Ubiquitin binding mediates the NF-κB inhibitory potential of ABIN proteins. Oncogene 27, 3739–3745 (2008). https://doi.org/10.1038/sj.onc.1211042

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