The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans
Article first published online: 18 SEP 2013
© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 13, Issue 1, pages 70–79, February 2014
How to Cite
Goh, G. Y. S., Martelli, K. L., Parhar, K. S., Kwong, A. W. L., Wong, M. A., Mah, A., Hou, N. S. and Taubert, S. (2014), The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans. Aging Cell, 13: 70–79. doi: 10.1111/acel.12154
- Issue published online: 16 JAN 2014
- Article first published online: 18 SEP 2013
- Accepted manuscript online: 19 AUG 2013 10:23PM EST
- Manuscript Accepted: 2 AUG 2013
- NIH Office of Research Infrastructure Programs. Grant Number: P40 OD010440
- CIHR. Grant Number: MOP-93713
- UBC and CFRI scholarships
- daf-2 ;
- Mediator complex;
- nuclear hormone receptor;
- oxidative stress;
Reactive oxygen species (ROS) play important signaling roles in metazoans, but also cause significant molecular damage. Animals tightly control ROS levels using sophisticated defense mechanisms, yet the transcriptional pathways that induce ROS defense remain incompletely understood. In the nematode Caenorhabditis elegans, the transcription factor SKN-1 is considered a master regulator for detoxification and oxidative stress responses. Here, we show that MDT-15, a subunit of the conserved Mediator complex, is also required for oxidative stress responses in nematodes. Specifically, mdt-15 is required to express SKN-1 targets upon chemical and genetic increase in SKN-1 activity. mdt-15 is also required to express genes in SKN-1-dependent and SKN-1-independent fashions downstream of insulin/IGF-1 signaling and for the longevity of daf-2/insulin receptor mutants. At the molecular level, MDT-15 binds SKN-1 through a region distinct from the classical transcription-factor-binding KIX-domain. Moreover, mdt-15 is essential for the transcriptional response to and survival on the organic peroxide tert-butyl-hydroperoxide (tBOOH), a largely SKN-1-independent response. The MDT-15 interacting nuclear hormone receptor, NHR-64, is specifically required for tBOOH but not arsenite resistance, but NHR-64 is dispensable for the transcriptional response to tBOOH. Hence, NHR-64 and MDT-15's mode of action remain elusive. Lastly, the role of MDT-15 in oxidative stress defense is functionally separable from its function in fatty acid metabolism, as exogenous polyunsaturated fatty acid complementation rescues developmental, but not stress sensitivity phenotypes of mdt-15 worms. Our findings reveal novel conserved players in the oxidative stress response and suggest a broad cytoprotective role for MDT-15.