title: Mammalian target of rapamycin complex 2 (mTORC2) negatively regulates Toll-like receptor 4-mediated inflammatory response via FoxO1.
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.
authors: Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
authors: Jonathan
authors: J
authors: Brown
authors: Huizhi
authors: H
authors: Wang
authors: Jill
authors: J
authors: Suttles
authors: Dana T
authors: DT
authors: Graves
authors: Michael
authors: M
authors: Martin
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D002352:Carrier Proteins; C504923:Crtc2 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D008070:Lipopolysaccharides; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; D014157:Transcription Factors; C440499:lipopolysaccharide, Escherichia coli O111 B4; C525637:rictor protein, mouse; D051057:Proto-Oncogene Proteins c-akt