RNA viruses: all bases covered?

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The cytoplasmic helicase proteins MDA5 and RIG-I have differential roles in viral dsRNA recognition.

The cytoplasmic pattern-recognition receptors melanoma-differentiation-associated protein 5 (MDA5) and retinoic-acid-inducible gene I (RIG-I) have both been shown to recognize polyinosinic–polycytidylic acid (poly I:C), which is a synthetic analogue of double-stranded RNA (dsRNA) that is used as a mimic of RNA-virus infection. In addition, RIG-I has been shown to be crucial for the recognition of several RNA viruses, but the function of MDA5 in vivo and the relationship between these two receptors in vivo were not known. Now, Shizuo Akira and colleagues show that MDA5 and RIG-I recognize different types of RNA virus and are important for host defence against these particular viruses.

To study the in vivo function of MDA5, the authors generated MDA5-deficient mice and examined their response, together with the response of RIG-I-deficient mice, to poly I:C. In support of previous (in vitro) studies, MDA5 was shown to be crucial for the production of type I interferons (that is, IFN alpha and IFN beta ), an early step in antiviral immune responses. However, in contrast to these previous in vitro studies, RIG-I was found to be dispensable for poly-I:C-induced type-I-IFN production in vivo. Furthermore, RIG-I was shown to be required for IFN beta production by mouse embryonic fibroblasts (MEFs) in response to in vitro-transcribed dsRNAs, whereas MDA5 was not. Taken together, these results indicate that MDA5 and RIG-I can detect different types of dsRNA.

This finding raised the possibility that these receptors recognize different RNA viruses, so the authors assessed the cytokine response of MEFs to single-stranded RNA (ssRNA) viruses (for which dsRNA is a replication intermediate) belonging to various virus families. RIG-I, but not MDA5, was required for the detection of several negative-sense ssRNA viruses (including influenza virus) and a positive-sense ssRNA virus, Japanese encephalitis virus (which is a flavivirus). By contrast, MDA5, but not RIG-I, was required for the detection of a positive-sense ssRNA virus, encephalomyocarditis virus (which is a picornavirus). Moreover, RIG-I-deficient mice and MDA5-deficient mice were highly susceptible to infection with the respective viruses, confirming that this receptor-mediated viral recognition has an important role in host defence.

MDA5 and RIG-I are therefore crucial for the recognition of different groups of viruses. How these receptors detect different viral RNAs remains unclear, and the authors suggest that analysing the crystal structures of the helicase (RNA-binding) domains of these proteins might shed light on the molecular mechanisms of this differential recognition.

Davina Dadley-Moore

References

Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101-105 (04 May 2006)