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Virus-Cell Interactions

Inhibition of Stress Granule Formation by Middle East Respiratory Syndrome Coronavirus 4a Accessory Protein Facilitates Viral Translation, Leading to Efficient Virus Replication

Keisuke Nakagawa, Krishna Narayanan, Masami Wada, Shinji Makino
Tom Gallagher, Editor
Keisuke Nakagawa
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA
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Krishna Narayanan
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA
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Masami Wada
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA
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Shinji Makino
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USACenter for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston, Texas, USAUTMB Center for Tropical Diseases, The University of Texas Medical Branch, Galveston, Texas, USASealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, Texas, USAThe Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, Texas, USA
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Tom Gallagher
Loyola University Medical Center
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DOI: 10.1128/JVI.00902-18
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ABSTRACT

Stress granule (SG) formation is generally triggered as a result of stress-induced translation arrest. The impact of SG formation on virus replication varies among different viruses, and the significance of SGs in coronavirus (CoV) replication is largely unknown. The present study examined the biological role of SGs in Middle East respiratory syndrome (MERS)-CoV replication. The MERS-CoV 4a accessory protein is known to inhibit SG formation in cells in which it was expressed by binding to double-stranded RNAs and inhibiting protein kinase R (PKR)-mediated phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Replication of MERS-CoV lacking the genes for 4a and 4b (MERS-CoV-Δp4), but not MERS-CoV, induced SG accumulation in MERS-CoV-susceptible HeLa/CD26 cells, while replication of both viruses failed to induce SGs in Vero cells, demonstrating cell type-specific differences in MERS-CoV-Δp4-induced SG formation. MERS-CoV-Δp4 replicated less efficiently than MERS-CoV in HeLa/CD26 cells, and inhibition of SG formation by small interfering RNA-mediated depletion of the SG components promoted MERS-CoV-Δp4 replication, demonstrating that SG formation was detrimental for MERS-CoV replication. Inefficient MERS-CoV-Δp4 replication was not due to either the induction of type I and type III interferons or the accumulation of viral mRNAs in the SGs. Rather, it was due to the inefficient translation of viral proteins, which was caused by high levels of PKR-mediated eIF2α phosphorylation and likely by the confinement of various factors that are required for translation in the SGs. Finally, we established that deletion of the 4a gene alone was sufficient for inducing SGs in infected cells. Our study revealed that 4a-mediated inhibition of SG formation facilitates viral translation, leading to efficient MERS-CoV replication.

IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) causes respiratory failure with a high case fatality rate in patients, yet effective antivirals and vaccines are currently not available. Stress granule (SG) formation is one of the cellular stress responses to virus infection and is generally triggered as a result of stress-induced translation arrest. SGs can be beneficial or detrimental for virus replication, and the biological role of SGs in CoV infection is unclear. The present study showed that the MERS-CoV 4a accessory protein, which was reported to block SG formation in cells in which it was expressed, inhibited SG formation in infected cells. Our data suggest that 4a-mediated inhibition of SG formation facilitates the translation of viral mRNAs, resulting in efficient virus replication. To our knowledge, this report is the first to show the biological significance of SG in CoV replication and provides insight into the interplay between MERS-CoV and antiviral stress responses.

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Inhibition of Stress Granule Formation by Middle East Respiratory Syndrome Coronavirus 4a Accessory Protein Facilitates Viral Translation, Leading to Efficient Virus Replication
Keisuke Nakagawa, Krishna Narayanan, Masami Wada, Shinji Makino
Journal of Virology Sep 2018, 92 (20) e00902-18; DOI: 10.1128/JVI.00902-18

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Inhibition of Stress Granule Formation by Middle East Respiratory Syndrome Coronavirus 4a Accessory Protein Facilitates Viral Translation, Leading to Efficient Virus Replication
Keisuke Nakagawa, Krishna Narayanan, Masami Wada, Shinji Makino
Journal of Virology Sep 2018, 92 (20) e00902-18; DOI: 10.1128/JVI.00902-18
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KEYWORDS

MERS coronavirus
accessory protein
stress granules

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