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Journal of Virology, October 2009, p. 10761-10769, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.00770-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Activation of MDA5 Requires Higher-Order RNA Structures Generated during Virus Infection{triangledown}

Andreas Pichlmair,1,2 Oliver Schulz,1 Choon-Ping Tan,1,{dagger} Jan Rehwinkel,1 Hiroki Kato,3 Osamu Takeuchi,3 Shizuo Akira,3 Michael Way,4 Giampietro Schiavo,5 and Caetano Reis e Sousa1*

Immunobiology Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom,1 Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria,2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Osaka 565-0871, Japan,3 Cell Motility Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom,4 Molecular Neuropathobiology Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom5

Received 16 April 2009/ Accepted 30 July 2009

Recognition of virus presence via RIG-I (retinoic acid inducible gene I) and/or MDA5 (melanoma differentiation-associated protein 5) initiates a signaling cascade that culminates in transcription of innate response genes such as those encoding the alpha/beta interferon (IFN-{alpha}/β) cytokines. It is generally assumed that MDA5 is activated by long molecules of double-stranded RNA (dsRNA) produced by annealing of complementary RNAs generated during viral infection. Here, we used an antibody to dsRNA to show that the presence of immunoreactivity in virus-infected cells does indeed correlate with the ability of RNA extracted from these cells to activate MDA5. Furthermore, RNA from cells infected with encephalomyocarditis virus or with vaccinia virus and precipitated with the anti-dsRNA antibody can bind to MDA5 and induce MDA5-dependent IFN-{alpha}/β production upon transfection into indicator cells. However, a prominent band of dsRNA apparent in cells infected with either virus does not stimulate IFN-{alpha}/β production. Instead, stimulatory activity resides in higher-order structured RNA that contains single-stranded RNA and dsRNA. These results suggest that MDA5 activation requires an RNA web rather than simply long molecules of dsRNA.

* Corresponding author. Mailing address: Immunobiology Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: 44 20 7269 2832. Fax: 44 20 7269 2833. E-mail: caetano{at}cancer.org.uk

{triangledown} Published ahead of print on 5 August 2009.

{dagger} Present address: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.

Journal of Virology, October 2009, p. 10761-10769, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.00770-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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