Tags

Type your tag names separated by a space and hit enter

Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans.
Biochem J 2008; 409(1):205-13BJ

Abstract

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.

Authors+Show Affiliations

Institute for Behavioral Genetics, University of Colorado at Boulder, Box 447, Boulder, CO 80309, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17714076

Citation

Kahn, Nate W., et al. "Proteasomal Dysfunction Activates the Transcription Factor SKN-1 and Produces a Selective Oxidative-stress Response in Caenorhabditis Elegans." The Biochemical Journal, vol. 409, no. 1, 2008, pp. 205-13.
Kahn NW, Rea SL, Moyle S, et al. Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans. Biochem J. 2008;409(1):205-13.
Kahn, N. W., Rea, S. L., Moyle, S., Kell, A., & Johnson, T. E. (2008). Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans. The Biochemical Journal, 409(1), pp. 205-13.
Kahn NW, et al. Proteasomal Dysfunction Activates the Transcription Factor SKN-1 and Produces a Selective Oxidative-stress Response in Caenorhabditis Elegans. Biochem J. 2008 Jan 1;409(1):205-13. PubMed PMID: 17714076.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans. AU - Kahn,Nate W, AU - Rea,Shane L, AU - Moyle,Sarah, AU - Kell,Alison, AU - Johnson,Thomas E, PY - 2007/8/24/pubmed PY - 2008/1/9/medline PY - 2007/8/24/entrez SP - 205 EP - 13 JF - The Biochemical journal JO - Biochem. J. VL - 409 IS - 1 N2 - 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. SN - 1470-8728 UR - https://www.unboundmedicine.com/medline/citation/17714076/Proteasomal_dysfunction_activates_the_transcription_factor_SKN_1_and_produces_a_selective_oxidative_stress_response_in_Caenorhabditis_elegans_ L2 - https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BJ20070521 DB - PRIME DP - Unbound Medicine ER -