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Journal Article

In vivo ligands of MDA5 and RIG-I in measles virus-infected cells.

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Söding,  J.
Research Group of Computational Biology, MPI for Biophysical Chemistry, Max Planck Society;

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2066581.pdf
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Supplementary Material (public)

2086581_Suppl.zip
(Supplementary material), 18MB

Citation

Runge, S., Sparrer, K. M. J., Lässig, C., Hembach, K., Baum, A., Garcia-Sastre, A., et al. (2014). In vivo ligands of MDA5 and RIG-I in measles virus-infected cells. PLoS Pathogens, 10(4): e1004081. doi:10.1371/journal.ppat.1004081.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0024-AF43-0
Abstract
RIG-I-like receptors (RLRs: RIG-I, MDA5 and LGP2) play a major role in the innate immune response against viral infections and detect patterns on viral RNA molecules that are typically absent from host RNA. Upon RNA binding, RLRs trigger a complex downstream signaling cascade resulting in the expression of type I interferons and proinflammatory cytokines. In the past decade extensive efforts were made to elucidate the nature of putative RLR ligands. In vitro and transfection studies identified 5′-triphosphate containing blunt-ended double-strand RNAs as potent RIG-I inducers and these findings were confirmed by next-generation sequencing of RIG-I associated RNAs from virus-infected cells. The nature of RNA ligands of MDA5 is less clear. Several studies suggest that double-stranded RNAs are the preferred agonists for the protein. However, the exact nature of physiological MDA5 ligands from virus-infected cells needs to be elucidated. In this work, we combine a crosslinking technique with next-generation sequencing in order to shed light on MDA5-associated RNAs from human cells infected with measles virus. Our findings suggest that RIG-I and MDA5 associate with AU-rich RNA species originating from the mRNA of the measles virus L gene. Corresponding sequences are poorer activators of ATP-hydrolysis by MDA5 in vitro, suggesting that they result in more stable MDA5 filaments. These data provide a possible model of how AU-rich sequences could activate type I interferon signaling.