Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans

Nate W. Kahn, Shane L. Rea, Sarah Moyle, Alison Kell, Thomas E. Johnson

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

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 downregulation 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 byproducts 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.

Original languageEnglish (US)
Pages (from-to)205-213
Number of pages9
JournalBiochemical Journal
Volume409
Issue number1
DOIs
StatePublished - Jan 1 2008

Keywords

  • 3H-1,2-dithiole-3-thione (D3T)
  • Chaperonin
  • Nuclear factor-E2 (NF-E2)-related factor 2 (NRF2)
  • Proteasome
  • SKN-1
  • gst-4

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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