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

S. Wagner, I. Carpentier, V. Rogov, M. Kreike, F. Ikeda, F. Löhr, C. J. Wu, J. D. Ashwell, V. Dötsch, I. Dikic, R. Beyaert

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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.

Original languageEnglish
Pages (from-to)3739-3745
Number of pages7
JournalOncogene
Volume27
Issue number26
DOIs
Publication statusPublished - Jun 12 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Wagner, S., Carpentier, I., Rogov, V., Kreike, M., Ikeda, F., Löhr, F., Wu, C. J., Ashwell, J. D., Dötsch, V., Dikic, I., & Beyaert, R. (2008). Ubiquitin binding mediates the NF-κB inhibitory potential of ABIN proteins. Oncogene, 27(26), 3739-3745. https://doi.org/10.1038/sj.onc.1211042