title: Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation.
abstract: LUBAC (linear ubiquitin chain assembly complex) activates the canonical NF-κB pathway through linear polyubiquitination of NEMO (NF-κB essential modulator, also known as IKKγ) and RIP1. However, the regulatory mechanism of LUBAC-mediated NF-κB activation remains elusive. Here, we show that A20 suppresses LUBAC-mediated NF-κB activation by binding linear polyubiquitin via the C-terminal seventh zinc finger (ZF7), whereas CYLD suppresses it through deubiquitinase (DUB) activity. We determined the crystal structures of A20 ZF7 in complex with linear diubiquitin at 1.70-1.98 Å resolutions. The crystal structures revealed that A20 ZF7 simultaneously recognizes the Met1-linked proximal and distal ubiquitins, and that genetic mutations associated with B cell lymphomas map to the ubiquitin-binding sites. Our functional analysis indicated that the binding of A20 ZF7 to linear polyubiquitin contributes to the recruitment of A20 into a TNF receptor (TNFR) signalling complex containing LUBAC and IκB kinase (IKK), which results in NF-κB suppression. These findings provide new insight into the regulation of immune and inflammatory responses.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan. ftokunaga@gunma-u.ac.jp
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tokunaga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishimasu
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Ishitani
authors.forename: Eiji
authors.initials: E
authors.lastname: Goto
authors.forename: Takuya
authors.initials: T
authors.lastname: Noguchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mio
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kamei
authors.forename: Averil
authors.initials: A
authors.lastname: Ma
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
mesh_terms: D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000235:genetics; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025821:Polyubiquitin / Q000096:biosynthesis; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism; D016335:Zinc Fingers / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D018124:Receptors, Tumor Necrosis Factor; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D025821:Polyubiquitin; D051550:I-kappa B Kinase; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3