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Sci. Signal., 21 January 2014
Vol. 7, Issue 309, p. ra8
Roquin-2 Promotes Ubiquitin-Mediated Degradation of ASK1 to Regulate Stress Responses
Atsushi Matsuzawa1, and
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.
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.
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).
Jishnu Das, Tommy V. Vo, Xiaomu Wei, Joseph C. Mellor, Virginia Tong, Andrew G. Degatano, Xiujuan Wang, Lihua Wang, Nicolas A. Cordero, Nathan Kruer-Zerhusen, Akihisa Matsuyama, Jeffrey A. Pleiss, Steven M. Lipkin, Minoru Yoshida, Frederick P. Roth, and Haiyuan Yu (21 May 2013) Sci. Signal.6 (276), ra38.
[DOI: 10.1126/scisignal.2003350] |Editor's Summary »|Abstract »|Full Text »|PDF »|Supplementary Materials »