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Sci. Signal., 21 January 2014
Vol. 7, Issue 309, p. ra8
[DOI: 10.1126/scisignal.2004822]

RESEARCH ARTICLES

Roquin-2 Promotes Ubiquitin-Mediated Degradation of ASK1 to Regulate Stress Responses

Takeshi Maruyama1, Toshihiro Araki1, Yosuke Kawarazaki1, Isao Naguro1, Susanne Heynen2, Pedro Aza-Blanc2, Ze’ev Ronai2, Atsushi Matsuzawa1, and Hidenori Ichijo1*

1 Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
2 Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

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 ubiquitin-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 (mitogen-activated 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.

* Corresponding author. E-mail: ichijo{at}mol.f.u-tokyo.ac.jp

Citation: T. Maruyama, T. Araki, Y. Kawarazaki, I. Naguro, S. Heynen, P. Aza-Blanc, Z. Ronai, A. Matsuzawa, H. Ichijo, Roquin-2 Promotes Ubiquitin-Mediated Degradation of ASK1 to Regulate Stress Responses. Sci. Signal. 7, ra8 (2014).

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