Activation of MDA5 requires higher-order RNA structures generated during virus infection

Andreas Pichlmair, Oliver Schulz, Choon Ping Tan, Jan Rehwinkel, Hiroki Kato, Osamu Takeuchi, Shizuo Akira, Michael Way, Giampietro Schiavo, Caetano Reis E Sousa

Research output: Contribution to journalArticlepeer-review

376 Scopus citations

Abstract

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-α/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-α/β production upon transfection into indicator cells. However, a prominent band of dsRNA apparent in cells infected with either virus does not stimulate IFN-α/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.

Original languageEnglish
Pages (from-to)10761-10769
Number of pages9
JournalJournal of Virology
Volume83
Issue number20
DOIs
StatePublished - Oct 2009
Externally publishedYes

Fingerprint

Dive into the research topics of 'Activation of MDA5 requires higher-order RNA structures generated during virus infection'. Together they form a unique fingerprint.

Cite this