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A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span
Maria K Lehtinen1, Zengqiang Yuan, Peter R Boag
1Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. Here, we demonstrate that the protein kinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors. MST1 phosphorylates FOXO proteins at a conserved site within the forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nuclear translocation, and thereby induces cell death in neurons. We also extend the MST-FOXO signaling link to nematodes. Knockdown of the C. elegans MST1 ortholog CST-1 shortens life span and accelerates tissue aging, while overexpression of cst-1 promotes life span and delays aging. The cst-1-induced life-span extension occurs in a daf-16-dependent manner. The identification of the FOXO transcription factors as major and evolutionarily conserved targets of MST1 suggests that MST kinases play important roles in diverse biological processes including cellular responses to oxidative stress and longevity.
Insights
The protein kinase MST1 triggers oxidative stress-induced cell death by activating FOXO transcription factors in neurons. This conserved MST-FOXO signaling pathway impacts aging and lifespan in C. elegans.
Area of Science:
- Cellular Biology
- Molecular Biology
- Neuroscience
Background:
- Oxidative stress significantly impacts cellular survival and homeostasis.
- The precise molecular mechanisms driving oxidative stress's biological effects require further elucidation.
Purpose of the Study:
- To identify the key mediators of oxidative stress-induced cell death in mammalian neurons.
- To investigate the role of the MST1-FOXO signaling pathway in cellular responses to oxidative stress and aging.
Main Methods:
- Investigated MST1's role in oxidative-stress-induced neuronal death using primary mammalian neurons.
- Analyzed FOXO protein phosphorylation, 14-3-3 binding, and nuclear translocation.
- Utilized C. elegans models to study the ortholog CST-1's effects on lifespan and aging, including DAF-16 dependency.
Main Results:
- MST1 directly activates FOXO transcription factors, mediating oxidative-stress-induced neuronal cell death.
- MST1 phosphorylates FOXO proteins, disrupting 14-3-3 interaction and promoting nuclear translocation.
- C. elegans CST-1 knockdown shortens lifespan and accelerates aging; CST-1 overexpression extends lifespan and delays aging in a DAF-16-dependent manner.
Conclusions:
- MST1 is a critical mediator of oxidative stress-induced cell death in neurons.
- The MST-FOXO signaling pathway is evolutionarily conserved and plays a significant role in regulating lifespan and aging.
- MST kinases are implicated in diverse biological processes, including cellular responses to oxidative stress and longevity.
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