Open AccessRegulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3
Author(s) -
Jee Hyun An,
Kelly C. Vranas,
Michael Lucke,
Hideki Inoue,
Naoki Hisamoto,
Kunihiro Matsumoto,
T. Keith Blackwell
Publication year - 2005
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0508105102
Subject(s) - caenorhabditis elegans , gsk 3 , biology , microbiology and biotechnology , protein kinase a , oxidative stress , glycogen synthase , oxidative phosphorylation , kinase , signal transduction , phosphorylation , biochemistry , gene
Oxidative stress plays a central role in many human diseases and in aging. InCaenorhabditis 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 theskn-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.