Central Regulatory Role for SIN1 in Interferon γ (IFNγ) Signaling and Generation of Biological Responses

J Biol Chem. 2017 Mar 17;292(11):4743-4752. doi: 10.1074/jbc.M116.757666. Epub 2017 Feb 7.


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.

Keywords: RNA editing; antiviral agent; innate immunity; interferon; signal transduction; translation control.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology*
  • Animals
  • Carrier Proteins / immunology*
  • Cell Line
  • Humans
  • Immunity, Innate
  • Interferon-gamma / immunology*
  • Mice
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / chemistry
  • Proto-Oncogene Proteins c-akt / immunology
  • STAT1 Transcription Factor / chemistry
  • STAT1 Transcription Factor / immunology
  • Signal Transduction


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • MAPKAP1 protein, human
  • STAT1 Transcription Factor
  • stress-activated protein kinase-interacting protein, mouse
  • Interferon-gamma
  • Proto-Oncogene Proteins c-akt