title: Ubiquitin binding mediates the NF-kappaB inhibitory potential of ABIN proteins.
abstract: Deregulated nuclear factor kappaB (NF-kappaB) activation plays an important role in inflammation and tumorigenesis. ABIN proteins have been characterized as negative regulators of NF-kappaB signaling. However, their mechanism of NF-kappaB 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-kappaB essential modulator/IkappaB kinase gamma (NEMO/IKKgamma) 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-kappaB inhibitory potential of ABINs. Taken together, these data illustrate an important role for ubiquitin binding in the negative regulation of NF-kappaB signaling by ABINs and identify UBAN as a novel UBD.
authors.affiliation: Institute for Biochemistry II, Goethe University Medical School, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wagner
authors.forename: I
authors.initials: I
authors.lastname: Carpentier
authors.forename: V
authors.initials: V
authors.lastname: Rogov
authors.forename: M
authors.initials: M
authors.lastname: Kreike
authors.forename: F
authors.initials: F
authors.lastname: Ikeda
authors.forename: F
authors.initials: F
authors.lastname: Löhr
authors.forename: C-J
authors.initials: CJ
authors.lastname: Wu
authors.forename: J D
authors.initials: JD
authors.lastname: Ashwell
authors.forename: V
authors.initials: V
authors.lastname: Dötsch
authors.forename: I
authors.initials: I
authors.lastname: Dikic
authors.forename: R
authors.initials: R
authors.lastname: Beyaert
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; C117046:TNIP1 protein, human; D025801:Ubiquitin