SKN-1 in the nematode worm Caenorhabditis elegans is functionally orthologous to mammalian NRF2 [NF-E2 (nuclear factor-E2)-related factor 2], a protein regulating response to oxidative stress. We have examined both the expression and activity of SKN-1 in response to a variety of oxidative stressors and to down-regulation of specific gene targets by RNAi (RNA interference). We used an SKN-1–GFP (green fluorescent protein) translational fusion to record changes in both skn-1 expression and SKN-1 nuclear localization, and a gst-4–GFP transcriptional fusion to measure SKN-1 transcriptional activity. GST-4 (glutathione transferase-4) is involved in the Phase II oxidative stress response and its expression is lost in an skn-1(zu67) mutant. In the present study, we show that the regulation of skn-1 is tied to the protein-degradation machinery of the cell. RNAi-targeted removal of most proteasome subunits in C. elegans caused nuclear localization of SKN-1 and, in some cases, induced transcription of gst-4. Most intriguingly, RNAi knockdown of proteasome core subunits caused nuclear localization of SKN-1 and induced gst-4, whereas RNAi knockdown of proteasome regulatory subunits resulted in nuclear localization of SKN-1 but did not induce gst-4. RNAi knockdown of ubiquitin-specific hydrolases and chaperonin components also caused nuclear localization of SKN-1 and, in some cases, also induced gst-4 transcription. skn-1 activation by proteasome dysfunction could be occurring by one or several mechanisms: (i) the reduced processivity of dysfunctional proteasomes may allow oxidatively damaged by-products to build up, which, in turn, activate the skn-1 stress response; (ii) dysfunctional proteasomes may activate the skn-1 stress response by blocking the constitutive turnover of SKN-1; and (iii) dysfunctional proteasomes may activate an unidentified signalling pathway that feeds back to control the skn-1 stress response.
Skip Nav Destination
Article navigation
January 2008
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
December 11 2007
Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans
Nate W. Kahn;
Nate W. Kahn
*Institute for Behavioral Genetics, University of Colorado at Boulder, Box 447, Boulder, CO 80309, U.S.A.
Search for other works by this author on:
Shane L. Rea;
Shane L. Rea
†Barshop Institute for Longevity and Aging Studies and Department of Physiology, University of Texas Health Science Center at San Antonio, Texas Research Park Campus, 15355 Lambda Drive, San Antonio, TX 78245-3207, U.S.A.
Search for other works by this author on:
Sarah Moyle;
Sarah Moyle
*Institute for Behavioral Genetics, University of Colorado at Boulder, Box 447, Boulder, CO 80309, U.S.A.
Search for other works by this author on:
Alison Kell;
Alison Kell
*Institute for Behavioral Genetics, University of Colorado at Boulder, Box 447, Boulder, CO 80309, U.S.A.
Search for other works by this author on:
Thomas E. Johnson
Thomas E. Johnson
1
*Institute for Behavioral Genetics, University of Colorado at Boulder, Box 447, Boulder, CO 80309, U.S.A.
1To whom correspondence should be addressed (email johnsont@colorado.edu).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
April 16 2007
Revision Received:
August 20 2007
Accepted:
August 23 2007
Accepted Manuscript online:
August 23 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 409 (1): 205–213.
Article history
Received:
April 16 2007
Revision Received:
August 20 2007
Accepted:
August 23 2007
Accepted Manuscript online:
August 23 2007
Citation
Nate W. Kahn, Shane L. Rea, Sarah Moyle, Alison Kell, Thomas E. Johnson; Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans. Biochem J 1 January 2008; 409 (1): 205–213. doi: https://doi.org/10.1042/BJ20070521
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.