Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation

Fuminori Tokunaga, Hiroshi Nishimasu, Ryuichiro Ishitani, Eiji Goto, Takuya Noguchi, Kazuhiro Mio, Kiyoko Kamei, Averil Ma, Kazuhiro Iwai, Osamu Nureki

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123 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3856-3870
Number of pages15
JournalEMBO Journal
Volume31
Issue number19
DOIs
Publication statusPublished - 2012 Oct 3

Keywords

  • A20
  • NF-κB
  • deubiquitinase
  • lymphoma
  • ubiquitin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Tokunaga, F., Nishimasu, H., Ishitani, R., Goto, E., Noguchi, T., Mio, K., Kamei, K., Ma, A., Iwai, K., & Nureki, O. (2012). Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation. EMBO Journal, 31(19), 3856-3870. https://doi.org/10.1038/emboj.2012.241