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The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells
Author(s) -
Veen Annemarthe G,
Maillard Pierre V,
Schmidt Jan Marten,
Lee Sonia A,
DeddoucheGrass Safia,
Borg Annabel,
Kjær Svend,
Snijders Ambrosius P,
Reis e Sousa Caetano
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201797479
Subject(s) - dicer , library science , rna interference , rna , biology , genetics , computer science , gene
In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG ‐I‐like receptor ( RLR ) family, which signal to induce production of type I interferons ( IFN ). These key antiviral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon‐stimulated genes ( ISG s), whose protein products restrict viral entry, replication and budding. ISG s include the RLR s themselves: RIG ‐I, MDA 5 and, the least‐studied family member, LGP 2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference ( RNA i). In RNA i, the endoribonuclease Dicer cleaves virus‐derived double‐stranded RNA (ds RNA ) into small interfering RNA s (si RNA s) that target complementary viral RNA for cleavage. Interestingly, the RNA i machinery is conserved in mammals, and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISG s act to mask or suppress antiviral RNA i. Here, we demonstrate that LGP 2 constitutes one of the ISG s that can inhibit antiviral RNA i in mammals. We show that LGP 2 associates with Dicer and inhibits cleavage of ds RNA into si RNA s both in vitro and in cells. Further, we show that in differentiated cells lacking components of the IFN response, ectopic expression of LGP 2 interferes with RNA i‐dependent suppression of gene expression. Conversely, genetic loss of LGP 2 uncovers ds RNA ‐mediated RNA i albeit less strongly than complete loss of the IFN system. Thus, the inefficiency of RNA i as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP 2 induced by type I IFN s. LGP 2‐mediated antagonism of ds RNA ‐mediated RNA i may help ensure that viral ds RNA substrates are preserved in order to serve as targets of antiviral ISG proteins.