Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3

Jae Hyung An, Kelly Vranas, Michael Lucke, Hideki Inoue, Naoki Hisamoto, Kunihiro Matsumoto, T. Keith Blackwell

Research output: Contribution to journalArticlepeer-review

152 Scopus citations

Abstract

Oxidative stress plays a central role in many human diseases and in aging. In Caenorhabditis elegans the SKN-1 protein induces phase II detoxification gene transcription, a conserved oxidative stress response, and is required for oxidative stress resistance and longevity. Oxidative stress induces SKN-1 to accumulate in intestinal nuclei, depending on p38 mitogen-activated protein kinase signaling. Here we show that, in the absence of stress, phosphorylation by glycogen synthase kinase-3 (GSK-3) prevents SKN-1 from accumulating in nuclei and functioning constitutively in the intestine. GSK-3 sites are conserved in mammalian SKN-1 orthologs, indicating that this level of regulation may be conserved. If inhibition by GSK-3 is blocked, background levels of p38 signaling are still required for SKN-1 function. WT and constitutively nuclear SKN-1 comparably rescue the skn-1 oxidative stress sensitivity, suggesting that an inducible phase II response may provide optimal stress protection. We conclude that (i) GSK-3 inhibits SKN-1 activity in the intestine, (ii) the phase II response integrates multiple regulatory signals, and (iii), by inhibiting this response, GSK-3 may influence redox conditions.

Original languageEnglish (US)
Pages (from-to)16275-16280
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number45
DOIs
StatePublished - Nov 8 2005
Externally publishedYes

Keywords

  • Longevity
  • p38 mitogen-activated protein kinase
  • Phase II gene
  • Stress response

ASJC Scopus subject areas

  • General

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