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

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)ra8
JournalScience Signaling
Volume7
Issue number309
DOIs
Publication statusPublished - 2014 Jan 21
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses'. Together they form a unique fingerprint.

  • Cite this

    Maruyama, T., Araki, T., Kawarazaki, Y., Naguro, I., Heynen, S., Aza-Blanc, P., Ronai, Z., Matsuzawa, A., & Ichijo, H. (2014). Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses. Science Signaling, 7(309), ra8. https://doi.org/10.1126/scisignal.2004822