Reciprocal Inhibition between Intracellular Antiviral Signaling and the RNAi Machinery in Mammalian Cells

RNA interference (RNAi) is an established antiviral defense mechanism in plants and invertebrates. Whether RNAi serves a similar function in mammalian cells remains unresolved. We find that in some cell types, mammalian RNAi activity is reduced shortly after viral infection via poly-ADP-ribosylation...

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Published inCell host & microbe Vol. 14; no. 4; pp. 435 - 445
Main Authors Seo, Gil Ju, Kincaid, Rodney P., Phanaksri, Teva, Burke, James M., Pare, Justin M., Cox, Jennifer E., Hsiang, Tien-Ying, Krug, Robert M., Sullivan, Christopher S.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 16.10.2013
Subjects
Cell Line
DNA Viruses - immunology
Humans
Interferons - immunology
Models, Biological
RNA Interference
RNA Viruses - immunology
RNA-Induced Silencing Complex - metabolism
Signal Transduction
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Summary:RNA interference (RNAi) is an established antiviral defense mechanism in plants and invertebrates. Whether RNAi serves a similar function in mammalian cells remains unresolved. We find that in some cell types, mammalian RNAi activity is reduced shortly after viral infection via poly-ADP-ribosylation of the RNA-induced silencing complex (RISC), a core component of RNAi. Well-established antiviral signaling pathways, including RIG-I/MAVS and RNaseL, contribute to inhibition of RISC. In the absence of virus infection, microRNAs repress interferon-stimulated genes (ISGs) associated with cell death and proliferation, thus maintaining homeostasis. Upon detection of intracellular pathogen-associated molecular patterns, RISC activity decreases, contributing to increased expression of ISGs. Our results suggest that, unlike in lower eukaryotes, mammalian RISC is not antiviral in some contexts, but rather RISC has been co-opted to negatively regulate toxic host antiviral effectors via microRNAs. [Display omitted] •Activation of antiviral signaling reduces RNAi activity in some mammalian cells•Antiviral signaling inhibits RNAi via poly-ADP-ribosylation of RISC, a core RNAi component•miRNAs negatively regulate cytotoxic interferon-stimulated genes (ISGs) in uninfected cells•Relief of miRNA action increases expression of some ISGs and enhances the antiviral response
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2013.09.002