TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains

Atsuhiro Kanayama, Rashu B. Seth, Lijun Sun, Chee Kwee Ea, Mei Hong, Abdullah Shaito, Yu Hsin Chiu, Li Deng, Zhijian J. Chen

Research output: Contribution to journalArticle

605 Scopus citations

Abstract

The activation of NF-κB and IKK requires an upstream kinase complex consisting of TAK1 and adaptor proteins such as TAB1, TAB2, or TAB3. TAK1 is in turn activated by TRAF6, a RING domain ubiquitin ligase that facilitates the synthesis of lysine 63-linked polyubiquitin chains. Here we present evidence that TAB2 and TAB3 are receptors that bind preferentially to lysine 63-linked polyubiquitin chains through a highly conserved zinc finger (ZnF) domain. Mutations of the ZnF domain abolish the ability of TAB2 and TAB3 to bind polyubiquitin chains, as well as their ability to activate TAK1 and IKK. Significantly, replacement of the ZnF domain with a heterologous ubiquitin binding domain restored the ability of TAB2 and TAB3 to activate TAK1 and IKK. We also show that TAB2 binds to polyubiquitinated RIP following TNFα stimulation. These results indicate that polyubiquitin binding domains represent a new class of signaling domains that regulate protein kinase activity through a nonproteolytic mechanism.

Original languageEnglish (US)
Pages (from-to)535-548
Number of pages14
JournalMolecular Cell
Volume15
Issue number4
DOIs
Publication statusPublished - Aug 27 2004

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology

Cite this