Central Regulatory Role for SIN1 in Interferon γ (IFNγ) Signaling and Generation of Biological Responses.
The precise signaling mechanisms by which type II IFN receptors control expression of unique genes to induce biological responses remain to be established. We provide evidence that Sin1, a known element of the mammalian target of rapamycin complex 2 (mTORC2), is required for IFNγ-induced phosphorylation and activation of AKT and that such activation mediates downstream regulation of mTORC1 and its effectors. These events play important roles in the assembly of the eukaryotic translation initiation factor 4F (eIF4F) and mRNA translation of IFN-stimulated genes. Interestingly, IFNγ-induced tyrosine phosphorylation of STAT1 is reduced in cells with targeted disruption of Sin1, leading to decreased transcription of several IFNγ-inducible genes in an mTORC2-independent manner. Additionally, our studies establish that Sin1 is essential for generation of type II IFN-dependent antiviral effects and antiproliferative responses in normal and malignant hematopoiesis. Together, our findings establish an important role for Sin1 in both transcription and translation of IFN-stimulated genes and type II IFN-mediated biological responses, involving both mTORC2-dependent and -independent functions.
From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, and.|the Department of Radiation Oncology, Northwestern University, Chicago, Illinois 60611.
Barbara
B
Kroczynska
From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, and.
Gavin T
GT
Blyth
From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, and.
Robert L
RL
Rafidi
the Toronto General Research Institute, University Health Network, and Department of Immunology, University of Toronto, Toronto, Ontario M5G 2M1, Canada.
Beata
B
Majchrzak-Kita
From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, and.
Lucy
L
Xu
From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, and.
Diana
D
Saleiro
From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, and.|the Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
Ewa M
EM
Kosciuczuk
the Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland.
Jacek
J
Jemielity
the Department of Immunobiology and the Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut 06520, and.|the Shanghai Institute of Immunology and Department of Microbiology and Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200000, China.
Bing
B
Su
From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, and.|the Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
Jessica K
JK
Altman
From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, and.|the Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
Elizabeth A
EA
Eklund
the Toronto General Research Institute, University Health Network, and Department of Immunology, University of Toronto, Toronto, Ontario M5G 2M1, Canada.
Eleanor N
EN
Fish
From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, and l-platanias@northwestern.edu.|the Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
Leonidas C
LC
Platanias
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000276:immunology; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor; C493277:MAPKAP1 protein, human; C561937:Mapkap1 protein, mouse
RNA editing; antiviral agent; innate immunity; interferon; signal transduction; translation control