Central Regulatory Role for SIN1 in Interferon {gamma} (IFN{gamma}) Signaling and Generation of Biological Responses [Cell Biology]

The precise signaling mechanisms by which Type II interferon (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 translation initiation factor 4F (eIF4F) and mRNA translation of ISGs. Interestingly, IFNγ-induced tyrosine phosphorylation of signal transducer and activator of transcription 1 (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 antiproli-ferative responses in normal and malignant hematopoiesis. Together, our findings establish an important role for Sin1 in both transcription and translation of ISGs and Type II IFN-mediated biological responses, involving both mTORC2-dependent and -independent functions.

from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2k0Tvjn
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