2016
DOI: 10.1371/journal.pbio.1002364
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An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway

Abstract: In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of ne… Show more

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Cited by 37 publications
(50 citation statements)
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References 71 publications
(94 reference statements)
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“…We show that induction of Ch25h by type I IFN plays a key role in restricting the SREBP2 pathway and cholesterol biosynthesis in the context of bacterial infection and LPS exposure. These observations are consistent with a number of recent studies that have demonstrated the ability of type I IFNs to repress cholesterol metabolism (Robertson et al, 2016)(York et al, 2015). However, our study suggests that Ch25h is not required to initiate suppression of sterol biosynthesis, but is instead required to maintain this effect over time.…”
Section: Discussionsupporting
confidence: 92%
“…We show that induction of Ch25h by type I IFN plays a key role in restricting the SREBP2 pathway and cholesterol biosynthesis in the context of bacterial infection and LPS exposure. These observations are consistent with a number of recent studies that have demonstrated the ability of type I IFNs to repress cholesterol metabolism (Robertson et al, 2016)(York et al, 2015). However, our study suggests that Ch25h is not required to initiate suppression of sterol biosynthesis, but is instead required to maintain this effect over time.…”
Section: Discussionsupporting
confidence: 92%
“…In a landmark paper, Ghazal and colleagues showed that virus-infected cells undergo Ifnar1-dependent reduction of mevalonic acid pathway flux, and that pathway inhibition impairs cytomegalovirus replication in a manner that can be reversed by metabolic rescue with geranylgeraniol (cell-permeant version of GGPP)[49]. By contrast, interferon-induced reduction in sterols mediates suppression of influenza A virus [50]. Interestingly, reduction in the pool size of newly synthesized cholesterol, either by interferon treatment or genetic intervention on the mevalonate pathway, promotes further interferon induction by activating the ER-resident immune receptor, STING [50].…”
Section: Mevalonic Acid Synthesis Pathway and Oxysterols In Antiviralmentioning
confidence: 99%
“…By contrast, interferon-induced reduction in sterols mediates suppression of influenza A virus [50]. Interestingly, reduction in the pool size of newly synthesized cholesterol, either by interferon treatment or genetic intervention on the mevalonate pathway, promotes further interferon induction by activating the ER-resident immune receptor, STING [50]. This finding suggests that the sterol and interferon networks communicate as a metabolic-immune circuit, and that ER cholesterol is detected not just by the classical SCAP-SREBP system, but also by innate immune receptors.…”
Section: Mevalonic Acid Synthesis Pathway and Oxysterols In Antiviralmentioning
confidence: 99%
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