Abstract
Type-I interferon (IFN)-induced activation of the mammalian target of rapamycin (mTOR) signaling pathway has been implicated in translational control of mRNAs encoding interferon-stimulated genes (ISGs). However, mTOR-sensitive translatomes commonly include mRNAs with a 5’ terminal oligopyrimidine tract (TOP), such as those encoding ribosomal proteins, but not ISGs. Because these translatomes were obtained under conditions when ISG expression is not induced, we examined the mTOR-sensitive translatome in human WISH cells stimulated with IFN β. The mTOR inhibitor Torin1 resulted in a repression of global protein synthesis, including that of ISG products, and translation of all but 3 ISG mRNAs (TLR3, NT5C3A, and RNF19B) was not selectively more sensitive to mTOR inhibition. Detailed studies of NT5C3A revealed an IFN-induced change in transcription start site resulting in a switch from a non-TOP to a TOP-like transcript variant and mTOR sensitive translation. Thus, we show that, in the cell model used, translation of the vast majority of ISG mRNAs is not selectively sensitive to mTOR activity and describe an uncharacterized mechanism wherein the 5’-UTR of an mRNA is altered in response to a cytokine, resulting in a shift from mTOR-insensitive to mTOR-sensitive translation.
Highlights
Upon type-I interferon (IFN) binding to its dimeric receptor IFNAR1:IFNAR2, the associated Janus kinases, Jak1 and Tyk2, are activated and phosphorylate IFNAR2 on tyrosine (Tyr) residues [1]
The findings presented appear to contradict previous reports suggesting that type-I IFN signaling hijacks the mammalian target of rapamycin (mTOR) pathway to selectively up-regulate the translational efficiency of interferon-stimulated genes (ISGs)
Our findings demonstrate that the vast majority of ISG-encoded mRNAs are no more reliant on the mTOR pathway than most other mRNAs
Summary
Upon type-I interferon (IFN) binding to its dimeric receptor IFNAR1:IFNAR2, the associated Janus kinases, Jak and Tyk, are activated and phosphorylate IFNAR2 on tyrosine (Tyr) residues [1] These phosphorylation sites serve as docking sites for Stat transcription factors, facilitating their phosphorylation by Jaks. Pharmacological inhibition, genetic knockout, and small interfering RNA (siRNA) knockdown have demonstrated that canonical PI3K-mTOR pathway components are required for IFN-induced cross-talk signaling [5]. These studies have demonstrated that altered murine ISG protein levels (e.g. Isg, Cxcl, Irf, Ifit, Slfn2) observed in mTOR pathway knockout cells after IFN stimulation are not the result of altered transcription, but rather translation. An RNA element or RNA binding protein mediating such selective activation of ISG translation has not been identified
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