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

Fuminori Tokunaga1, Hiroshi Nishimasu, Ryuichiro Ishitani

  • 1Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan. ftokunaga@gunma-u.ac.jp

The EMBO Journal
|October 4, 2012
PubMed

Insights

A20 protein suppresses NF-κB activation by binding linear ubiquitin chains, revealing new insights into immune and inflammatory response regulation. This mechanism involves A20

Area of Science:

  • Molecular Biology
  • Immunology
  • Structural Biology

Background:

  • The linear ubiquitin chain assembly complex (LUBAC) activates the canonical NF-κB pathway.
  • The precise regulatory mechanisms governing LUBAC-mediated NF-κB activation are not fully understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of LUBAC-mediated NF-κB activation.
  • To investigate the roles of A20 and CYLD in suppressing this pathway.

Main Methods:

  • Determined crystal structures of A20's seventh zinc finger (ZF7) in complex with linear diubiquitin.
  • Utilized functional analysis to assess the impact of A20 binding on NF-κB signaling.
  • Investigated the deubiquitinase (DUB) activity of CYLD.

Main Results:

  • A20 suppresses LUBAC-mediated NF-κB activation by binding linear polyubiquitin via its ZF7 domain.
  • Crystal structures reveal A20 ZF7 simultaneously recognizes Met1-linked ubiquitins, with disease-associated mutations mapping to these sites.
  • A20 binding to linear polyubiquitin facilitates its recruitment into TNF receptor signaling complexes, inhibiting NF-κB activation.

Conclusions:

  • A20 directly inhibits LUBAC-mediated NF-κB activation through specific binding to linear ubiquitin chains.
  • CYLD also suppresses this pathway via its deubiquitinase activity.
  • These findings offer novel insights into the regulation of immune and inflammatory responses.

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