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

doi:10.1073/pnas.0508105102

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

^*Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215; Departments of ^§Pathology and ^†Medicine, Harvard Medical School, Boston, MA 02115; and ^‡Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan

Communicated by Constance L. Cepko, Harvard Medical School, Boston, MA, September 19, 2005 (received for review June 21, 2005)

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.

Footnotes

↵ ¶ To whom correspondence should be sent at the * address. E-mail: keith.blackwell{at}joslin.harvard.edu.
Author contributions: T.K.B. designed research; J.H.A., K.V., and M.L. performed research; H.I., N.H., and K.M. contributed new reagents/analytic tools; J.H.A., K.M., and T.K.B. analyzed data; and J.H.A. and T.K.B. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations: GSK-3, glycogen synthase kinase-3; RNAi, RNA interference; GCS-1, γ-glutamylcysteine synthetase; Nrf, NF-E2-related factor; MAPK, mitogen-activated protein kinase.