TY - JOUR
T1 - Interferon inhibits a model RNA virus via a limited set of inducible effector genes
AU - McDougal, Matthew B.
AU - De Maria, Anthony M.
AU - Ohlson, Maikke B.
AU - Kumar, Ashwani
AU - Xing, Chao
AU - Schoggins, John W.
N1 - Publisher Copyright:
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
PY - 2023/9/6
Y1 - 2023/9/6
N2 - Interferons control viral infection by inducing the expression of antiviral effector proteins encoded by interferon-stimulated genes (ISGs). The field has mostly focused on identifying individual antiviral ISG effectors and defining their mechanisms of action. However, fundamental gaps in knowledge about the interferon response remain. For example, it is not known how many ISGs are required to protect cells from a particular virus, though it is theorized that numerous ISGs act in concert to achieve viral inhibition. Here, we used CRISPR-based loss-of-function screens to identify a markedly limited set of ISGs that confer interferon-mediated suppression of a model alphavirus, Venezuelan equine encephalitis virus (VEEV). We show via combinatorial gene targeting that three antiviral effectors—ZAP, IFIT3, and IFIT1—together constitute the majority of interferon-mediated restriction of VEEV, while accounting for < 0.5% of the interferon-induced transcriptome. Together, our data suggest a refined model of the antiviral interferon response in which a small subset of “dominant” ISGs may confer the bulk of the inhibition of a given virus.
AB - Interferons control viral infection by inducing the expression of antiviral effector proteins encoded by interferon-stimulated genes (ISGs). The field has mostly focused on identifying individual antiviral ISG effectors and defining their mechanisms of action. However, fundamental gaps in knowledge about the interferon response remain. For example, it is not known how many ISGs are required to protect cells from a particular virus, though it is theorized that numerous ISGs act in concert to achieve viral inhibition. Here, we used CRISPR-based loss-of-function screens to identify a markedly limited set of ISGs that confer interferon-mediated suppression of a model alphavirus, Venezuelan equine encephalitis virus (VEEV). We show via combinatorial gene targeting that three antiviral effectors—ZAP, IFIT3, and IFIT1—together constitute the majority of interferon-mediated restriction of VEEV, while accounting for < 0.5% of the interferon-induced transcriptome. Together, our data suggest a refined model of the antiviral interferon response in which a small subset of “dominant” ISGs may confer the bulk of the inhibition of a given virus.
KW - CRISPR-Cas9 screening
KW - Venezuelan equine encephalitis virus
KW - alphavirus
KW - interferon-stimulated genes
KW - virus–host interactions
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U2 - 10.15252/embr.202356901
DO - 10.15252/embr.202356901
M3 - Article
C2 - 37497756
AN - SCOPUS:85165875633
SN - 1469-221X
VL - 24
JO - EMBO Reports
JF - EMBO Reports
IS - 9
M1 - e56901
ER -