Distinct RIG-I and MDA5 Signaling by RNA Viruses in Innate Immunity
Open accessAbstract
Alpha/beta interferon immune defenses are essential for resistance to viruses and can be triggered through the actions of the cytoplasmic helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Signaling by each is initiated by the recognition of viral products such as RNA and occurs through downstream interaction with the IPS-1 adaptor protein. We directly compared the innate immune signaling requirements of representative viruses of the Flaviviridae , Orthomyxoviridae , Paramyxoviridae , and Reoviridae for RIG-I, MDA5, and interferon promoter-stimulating factor 1 (IPS-1). In cultured fibroblasts, IPS-1 was essential for innate immune signaling of downstream interferon regulatory factor 3 activation and interferon-stimulated gene expression, but the requirements for RIG-I and MDA5 were variable. Each was individually dispensable for signaling triggered by reovirus and dengue virus, whereas RIG-I was essential for signaling by influenza A virus, influenza B virus, and human respiratory syncytial virus. Functional genomics analyses identified cellular genes triggered during influenza A virus infection whose expression was strictly dependent on RIG-I and which are involved in processes of innate or adaptive immunity, apoptosis, cytokine signaling, and inflammation associated with the host response to contemporary and pandemic strains of influenza virus. These results define IPS-1-dependent signaling as an essential feature of host immunity to RNA virus infection. Our observations further demonstrate differential and redundant roles for RIG-I and MDA5 in pathogen recognition and innate immune signaling that may reflect unique and shared biologic properties of RNA viruses whose differential triggering and control of gene expression may impact pathogenesis and infection.
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RIG-I-deficient cells show reduced expression of IFN-alpha and -beta genes and IFN-stimulated genes during influenza virus infection.
“RIG-I-deficient cells show reduced expression of IFN-␣ and - genes as well as IFN-stimulated genes during influenza virus infection (91).”
From Into the Eye of the Cytokine Storm (2012) · cites this paper as [91]
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- Authors
- Loo, Y.-M., Fornek, J., Crochet, N., Bajwa, G., Perwitasari, O., Martinez-Sobrido, L., Akira, S., Gill, M. A., García-Sastre, A., Katze, M. G., & Gale, M.
- Affiliations
- University of Washington (US)
- Microbiology
- The University of Texas Southwestern Medical Center (US)
- Departments of Microbiology
- Corresponding author
- Gale, Michael
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2008-01
- Volume
- 82
- Issue
- 1
- Pages
- 335-345
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC2224404
- OpenAlex
- W2148985310
- Cited by
- 1,071
- References
- 43
- Citations by year
- 2026: 27 · 2025: 28 · 2024: 38 · 2023: 36 · 2022: 27 · 2021: 63 · 2020: 58 · 2019: 61 · 2018: 77 · 2017: 63 · 2016: 53 · 2015: 59 · 2014: 83 · 2013: 71 · 2012: 82
- FWCI
- 20.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Washington
- Wellcome Trust
- National Institutes of Health (U19 AI62623)
- National Cancer Institute (T32CA009229, CA09229-28)
- National Institute of Allergy and Infectious Diseases (U19 AI62623, R01 AI22646, R01AI060389, U19AI062623, R01AI022646, R01AI046954, R01-AI46954)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Keywords
- RIG-I, MDA5, IPS-1, interferon signaling, innate immunity, RNA viruses, IRF3, interferon-stimulated genes, influenza A virus, influenza B, respiratory syncytial virus, dengue virus, reovirus, flavivirus, orthomyxoviruses, paramyxovirus, host-virus interaction, functional genomics
- MeSH terms
- DEAD Box Protein 58, Interferon-Induced Helicase, IFIH1, Animals, Cells, Cultured, Fibroblasts, Gene Expression Regulation, Immunity, Innate, Mice, Inbred C57BL, Orthomyxoviridae, Paramyxoviridae, Reoviridae, RNA Viruses, Signal Transduction, Flaviviridae, Mice, Knockout, Adaptor Proteins, Signal Transducing, Interferon Regulatory Factor-3, Mice, DEAD-box RNA Helicases
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