title: Binding of OTULIN to the PUB domain of HOIP controls NF-κB signaling.
abstract: Linear ubiquitin chains are implicated in the regulation of the NF-κB pathway, immunity, and inflammation. They are synthesized by the LUBAC complex containing the catalytic subunit HOIL-1-interacting protein (HOIP) and are disassembled by the linear ubiquitin-specific deubiquitinase OTULIN. Little is known about the regulation of these opposing activities. Here we demonstrate that HOIP and OTULIN interact and act as a bimolecular editing pair for linear ubiquitin signals in vivo. The HOIP PUB domain binds to the PUB interacting motif (PIM) of OTULIN and the chaperone VCP/p97. Structural studies revealed the basis of high-affinity interaction with the OTULIN PIM. The conserved Tyr56 of OTULIN makes critical contacts with the HOIP PUB domain, and its phosphorylation negatively regulates this interaction. Functionally, HOIP binding to OTULIN is required for the recruitment of OTULIN to the TNF receptor complex and to counteract HOIP-dependent activation of the NF-κB pathway.
authors.affiliation: Institute of Biochemistry II, Goethe University Faculty of Medicine, 60590 Frankfurt am Main, Germany.
authors.forename: Veronique
authors.initials: V
authors.lastname: Schaeffer
authors.affiliation: Institute of Biochemistry II, Goethe University Faculty of Medicine, 60590 Frankfurt am Main, Germany; Buchmann Institute for Molecular Life Sciences, Goethe University, 60438 Frankfurt am Main, Germany.
authors.forename: Masato
authors.initials: M
authors.lastname: Akutsu
authors.affiliation: Institute of Biochemistry II, Goethe University Faculty of Medicine, 60590 Frankfurt am Main, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Olma
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Goethe University, 60438 Frankfurt am Main, Germany.
authors.forename: Ligia C
authors.initials: LC
authors.lastname: Gomes
authors.affiliation: Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, 305-0801, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kawasaki
authors.affiliation: Institute of Biochemistry II, Goethe University Faculty of Medicine, 60590 Frankfurt am Main, Germany; Buchmann Institute for Molecular Life Sciences, Goethe University, 60438 Frankfurt am Main, Germany. Electronic address: Ivan.Dikic@biochem2.de.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D013816:Thermodynamics; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C582107:OTULIN protein, human; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein