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

• Published in: Science signaling 2014-01, Vol.7 (309), p.ra8-ra8
• Main Authors: Maruyama, Takeshi, Araki, Toshihiro, Kawarazaki, Yosuke, Naguro, Isao, Heynen, Susanne, Aza-Blanc, Pedro, Ronai, Ze'ev, Matsuzawa, Atsushi, Ichijo, Hidenori
• Format: Article
• Language: English
• Subjects: Animals; Caenorhabditis elegans - genetics; Caenorhabditis elegans - microbiology; Cell Death - drug effects; Cell Line; Enzyme Activation; Humans; Hydrogen Peroxide - metabolism; MAP Kinase Kinase Kinase 5 - genetics; MAP Kinase Kinase Kinase 5 - metabolism; Mitogen-Activated Protein Kinases - metabolism; Oxidative Stress; Proteolysis; Reactive Oxygen Species - metabolism; Repressor Proteins - physiology; RNA, Small Interfering - genetics; Ubiquitin - metabolism; Ubiquitination
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.2004822

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.