Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses

Takeshi Maruyama, Toshihiro Araki, Yosuke Kawarazaki, Isao Naguro, Susanne Heynen, Pedro Aza-Blanc, Ze'ev Ronai, Atsushi Matsuzawa, Hidenori Ichijo*

*この研究の対応する著者

研究成果: Article査読

45 被引用数 (Scopus)

抄録

Apoptosis signal-regulating kinase 1 (ASK1, also known as MAP3K5) mediates reactive oxygen species (ROS)-induced cell death. When activated by ROS, ASK1 ultimately becomes ubiquitinated and degraded by the proteasome, a process that is antagonized by the biquitin-specific protease USP9X. Using a functional siRNA (small interfering RNA) screen in HeLa cells, we identified Roquin-2 (also called RC3H2) as an E3 ubiquitin ligase required for ROS-induced ubiquitination and degradation of ASK1. In cells treated with H2O2, knockdown of Roquin-2 promoted sustained activation of ASK1 and the downstream stress-responsive kinases JNK (c-Jun amino-terminal kinase) and p38 MAPK (mitogenactivated protein kinase), and led to cell death. The nematode Caenorhabditis elegans produces ROS as a defense mechanism in response to bacterial infection. In C. elegans, mutation of the gene encoding the Roquin-2 ortholog RLE-1 promoted accumulation of the activated form of the ASK1 ortholog NSY-1 and conferred resistance to infection by the bacteria Pseudomonas aeruginosa. Thus, these data suggest that degradation of ASK1 mediated by Roquin-2 is an evolutionarily conserved mechanism required for the appropriate regulation of stress responses, including pathogen resistance and cell death.

本文言語English
ページ(範囲)ra8
ジャーナルScience Signaling
7
309
DOI
出版ステータスPublished - 2014 1 21
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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