Ubiquitin-like Sequence in ASK1 Plays Critical Roles in the Recognition and Stabilization by USP9X and Oxidative Stress-Induced Cell Death

Hiroaki Nagai, Takuya Noguchi, Kengo Homma, Kazumi Katagiri, Kohsuke Takeda, Atsushi Matsuzawa, Hidenori Ichijo

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Ubiquitination is an important posttranslational modification that regulates various cellular processes, including signal transduction. However, physiological roles of ubiquitination in the regulation of MAPK pathways are poorly understood. Here, we identified the deubiquitinating enzyme USP9X as a binding partner of ASK1 that mediates oxidative stress-induced cell death through activation of the JNK and p38 MAPK pathways. In the recognition of ubiquitin by deubiquitinating enzymes, the importance of a tandem glycine-glycine sequence in the ubiquitin C terminus has been suggested. Interestingly, ASK1 contains six amino acids identical to the ubiquitin C terminus (LRLRGG), and the GG sequence of ASK1 was required for the USP9X-ASK1 interaction. We also found that USP9X interacted with oxidative stress-activated ASK1 and prevented it from undergoing ubiquitin-dependent degradation. In USP9X-deficient cells, oxidative stress-induced JNK activation and subsequent cell death were reduced. These results demonstrate that USP9X-dependent stabilization of activated ASK1 plays a crucial role in oxidative stress-induced cell death.

Original languageEnglish
Pages (from-to)805-818
Number of pages14
JournalMolecular Cell
Volume36
Issue number5
DOIs
Publication statusPublished - 2009 Dec 11
Externally publishedYes

Keywords

  • CELLCYCLE
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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