Abstract
We provide evidence for a unique pathway engaged by the type II IFN receptor, involving mTORC2/AKT-mediated downstream regulation of mTORC1 and effectors. These events are required for formation of the eukaryotic translation initiation factor 4F complex (eIF4F) and initiation of mRNA translation of type II interferon-stimulated genes. Our studies establish that Rictor is essential for the generation of type II IFN-dependent antiviral and antiproliferative responses and that it controls the generation of type II IFN-suppressive effects on normal and malignant hematopoiesis. Together, our findings establish a central role for mTORC2 in IFNγ signaling and type II IFN responses.
Keywords:
PI3K; antiviral agent; interferon; signal transduction; translation control; translation initiation factor.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / metabolism
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Carrier Proteins / metabolism*
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Chemokine CXCL10 / metabolism
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Eukaryotic Initiation Factor-4F / metabolism*
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Fibroblasts / metabolism
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Gene Expression Regulation
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Hematopoiesis
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Hematopoietic Stem Cells / cytology
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Humans
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Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism
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Interferon-gamma / metabolism*
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Mice
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Mice, Knockout
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Multiprotein Complexes / metabolism*
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Phosphorylation
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Polyribosomes / metabolism
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Protein Biosynthesis
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Rapamycin-Insensitive Companion of mTOR Protein
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Receptors, Interferon / metabolism*
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Signal Transduction*
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TOR Serine-Threonine Kinases / metabolism*
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U937 Cells
Substances
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Antiviral Agents
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Carrier Proteins
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Chemokine CXCL10
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Cxcl10 protein, mouse
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Eukaryotic Initiation Factor-4F
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IRF9 protein, mouse
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Interferon-Stimulated Gene Factor 3, gamma Subunit
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Multiprotein Complexes
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Rapamycin-Insensitive Companion of mTOR Protein
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Receptors, Interferon
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interferon receptor, type II
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rictor protein, mouse
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Interferon-gamma
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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TOR Serine-Threonine Kinases