Research ArticleStress Response

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

Sci. Signal.  21 Jan 2014:
Vol. 7, Issue 309, pp. ra8
DOI: 10.1126/scisignal.2004822

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ASK Under Stress

Cells produce reactive oxygen species (ROS) to defend against infection, but sustained ROS signaling such as that associated with oxidative stress can lead to cell death. ROS activates the protein kinase ASK1, which promotes phosphorylation of downstream stress-responsive proteins. However, prolonged ASK1 activity can lead to cell death, and ROS-induced degradation of ASK1 by the ubiquitin-proteasome pathway is required to prevent cell death. Maruyama et al. identified Roquin-2 in a screen in human cultured cells of E3 ligases that promote ASK1 degradation. Roquin-2 promoted the ubiquitination of ROS-activated ASK1, and loss of Roquin-2 increased the abundance of ASK1, sustained the activation of downstream proteins, and reduced viability in human cancer cells exposed to exogenous ROS. In worms, genetic ablation of the Caenorhabditis elegans homolog of Roquin-2 increased the abundance of ASK1 and delayed the death of worms after exposure to lethal bacteria. Knocking down ASK1 in Roquin-2–deficient worms increased susceptibility to death due to bacterial infection. Thus, the ability of Roquin-2 to control ASK1 activity is an evolutionarily conserved module involved in oxidative signaling responses.