Abstract
Forkhead transcription factors (FOXOs) alter a diverse array of cellular processes including the cell cycle, oxidative stress resistance, and aging. Insulin/Akt activation directs phosphorylation and cytoplasmic sequestration of FOXO away from its target genes and serves as an endpoint of a complex signaling network. Using a human genome small interfering RNA (siRNA) library in a cell-based assay, we identified an extensive network of proteins involved in nuclear export, focal adhesion, and mitochondrial respiration not previously implicated in FOXO localization. Furthermore, a detailed examination of mitochondrial factors revealed that loss of uncoupling protein 5 (UCP5) modifies the energy balance and increases free radicals through up-regulation of uncoupling protein 3 (UCP3). The increased superoxide content induces c-Jun N-terminal kinase 1 (JNK1) kinase activity, which in turn affects FOXO localization through a compensatory dephosphorylation of Akt. The resulting nuclear FOXO increases expression of target genes, including mitochondrial superoxide dismutase. By connecting free radical defense and mitochondrial uncoupling to Akt/FOXO signaling, these results have implications in obesity and type 2 diabetes development and the potential for therapeutic intervention.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Active Transport, Cell Nucleus / genetics
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Adenosine Triphosphate / biosynthesis
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Adenosine Triphosphate / genetics
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Cell Line
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Electron Transport Chain Complex Proteins / genetics*
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Electron Transport Chain Complex Proteins / metabolism
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Forkhead Box Protein O1
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Forkhead Transcription Factors / metabolism*
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Genome-Wide Association Study*
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Humans
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Ion Channels / genetics
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Ion Channels / metabolism
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Membrane Potential, Mitochondrial / genetics
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism
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Mitochondria / genetics
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Mitochondria / metabolism*
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mitochondrial Uncoupling Proteins
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Mitogen-Activated Protein Kinase 8 / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Oxidative Phosphorylation
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Protein Transport / genetics
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA Interference
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RNA, Small Interfering / genetics*
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Signal Transduction / genetics*
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Uncoupling Protein 3
Substances
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Electron Transport Chain Complex Proteins
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FOXO1 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Ion Channels
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Membrane Transport Proteins
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Mitochondrial Proteins
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Mitochondrial Uncoupling Proteins
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Nerve Tissue Proteins
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RNA, Small Interfering
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SLC25A14 protein, human
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UCP3 protein, human
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Uncoupling Protein 3
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Adenosine Triphosphate
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 8