Abstract
Activation of the PI3K pathway plays a pivotal role in regulating the inflammatory response. The loss of mTORC2 has been shown to abrogate the activation of Akt, a critical downstream component of PI3K signaling. However, the biological importance of mTORC2 in innate immunity is currently unknown. Here we demonstrate that rictor, a key component of mTORC2, plays a critical role in controlling the innate inflammatory response via its ability to regulate FoxO1. Upon LPS stimulation, both rictor-deficient mouse embryonic fibroblasts (MEFs) and rictor knockdown dendritic cells exhibited a hyperinflammatory phenotype. The hyperinflammatory phenotype was due to a defective Akt signaling axis, because both rictor-deficient MEFs and rictor knockdown dendritic cells exhibited attenuated Akt phosphorylation and kinase activity. Analysis of downstream Akt targets revealed that phosphorylation of FoxO1 was impaired in rictor-deficient cells, resulting in elevated nuclear FoxO1 levels and diminished nuclear export of FoxO1 upon LPS stimulation. Knockdown of FoxO1 attenuated the hyperinflammatory phenotype exhibited by rictor-deficient MEFs. Moreover, FoxO1 deletion in dendritic cells attenuated the capacity of LPS to induce inflammatory cytokine expression. These findings identify a novel signaling pathway by which mTORC2 regulates the TLR-mediated inflammatory response through its ability to regulate FoxO1.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Carrier Proteins / metabolism
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Embryo, Mammalian / cytology
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Embryo, Mammalian / immunology
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Embryo, Mammalian / metabolism
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Fibroblasts / cytology
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Fibroblasts / immunology
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Fibroblasts / metabolism
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Forkhead Box Protein O1
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology*
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Forkhead Transcription Factors / metabolism
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Immunity, Innate / drug effects
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Immunity, Innate / genetics
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Immunity, Innate / immunology*
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Inflammation / chemically induced
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism
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Lipopolysaccharides / pharmacology
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Mice
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Mice, Transgenic
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Phosphorylation / drug effects
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Phosphorylation / genetics
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Phosphorylation / immunology
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-akt / metabolism
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Rapamycin-Insensitive Companion of mTOR Protein
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology*
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Toll-Like Receptor 4 / metabolism
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Trans-Activators / genetics
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Trans-Activators / immunology*
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Trans-Activators / metabolism
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Transcription Factors
Substances
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Carrier Proteins
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Crtc2 protein, mouse
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Lipopolysaccharides
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Rapamycin-Insensitive Companion of mTOR Protein
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Trans-Activators
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Transcription Factors
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lipopolysaccharide, Escherichia coli O111 B4
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rictor protein, mouse
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Proto-Oncogene Proteins c-akt