TY - JOUR
T1 - Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3
AU - An, Jae Hyung
AU - Vranas, Kelly
AU - Lucke, Michael
AU - Inoue, Hideki
AU - Hisamoto, Naoki
AU - Matsumoto, Kunihiro
AU - Blackwell, T. Keith
PY - 2005/11/8
Y1 - 2005/11/8
N2 - 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.
AB - 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.
KW - Longevity
KW - Phase II gene
KW - Stress response
KW - p38 mitogen-activated protein kinase
UR - http://www.scopus.com/inward/record.url?scp=28044446334&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28044446334&partnerID=8YFLogxK
U2 - 10.1073/pnas.0508105102
DO - 10.1073/pnas.0508105102
M3 - Article
C2 - 16251270
AN - SCOPUS:28044446334
SN - 0027-8424
VL - 102
SP - 16275
EP - 16280
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -