MDA5 plays a crucial role in enterovirus 71 RNA-mediated IRF3 activation.

Abstract

Induction of type-I interferons (IFNs), IFN-α/β, is crucial to innate immunity against RNA virus infection. Cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors, including RIG-I and melanoma differentiation-associated gene 5 (MDA5), are critical pathogen sensors for activation of type-I IFN expression in response to RNA virus infection. MDA5 is required for type-I IFN expression in mouse models in response to infection by picornaviruses, such as encephalomyocarditis virus (EMCV) and coxsackievirus B3. Enterovirus 71 (EV71) belongs to picornaviridae and contains positive-stranded RNA genome that is linked with VPg protein at the 5' end. Although a recent study showed that EV71 3C protease could suppress RIG-I-mediated IFN-β response, the cytoplasmic RIG-I-like receptor that is directly involved in the recognition of EV71 RNA remains unclear. Using EV71-derived RNA as an agonist, we demonstrate that MDA5 is involved in EV71 RNA-mediated IRF3 activation and IFN-β transcription. Our data also show that overexpression of the MDA5 protein reverses the suppression of IRF3 activation caused by EV71 infection. These results indicate that MDA5 is an important factor for EV71 RNA-activated type-I IFN expression. Furthermore, we also show that EV71 infection enhances MDA5 degradation and that the degradation could be inhibited by a broad spectrum caspase inhibitor.

• Authors: Rei-Lin Kuo, Li-Ting Kao, Sue-Jane Lin, Robert Yung-Liang Wang, Shin-Ru Shih
• Journal: PloS one (PLoS One) Vol. 8 Issue 5 Pg. e63431 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23650567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IRF3 protein, human
• Interferon Regulatory Factor-3
• RNA, Viral
• Receptors, Immunologic
• Interferon-beta
• Caspases
• DDX58 protein, human
• IFIH1 protein, human
• DEAD Box Protein 58
• DEAD-box RNA Helicases
• Interferon-Induced Helicase, IFIH1

Topics

• Caspases (metabolism)
• DEAD Box Protein 58
• DEAD-box RNA Helicases (genetics, metabolism, physiology)
• Enterovirus A, Human (genetics, immunology)
• Enterovirus Infections (immunology, virology)
• HeLa Cells
• Host-Pathogen Interactions
• Humans
• Immunity, Innate
• Interferon Regulatory Factor-3 (genetics, metabolism)
• Interferon-Induced Helicase, IFIH1
• Interferon-beta (genetics, metabolism)
• Proteolysis
• RNA, Viral (genetics)
• Receptors, Immunologic
• Transcriptional Activation