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The Dengue Virus Replication Complex: From RNA Replication to Protein-Protein Interactions to Evasion of Innate Immunity

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Dengue and Zika: Control and Antiviral Treatment Strategies

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1062))

Abstract

Viruses from the Flavivirus family are the causative agents of dengue fever, Zika, Japanese encephalitis, West Nile encephalitis or Yellow fever and constitute major or emerging public health problems. A better understanding of the flavivirus replication cycle is likely to offer new opportunities for the design of antiviral therapies to treat severe conditions provoked by these viruses, but it should also help reveal fundamental biological mechanisms of the host cell. During virus replication, RNA synthesis is mediated by a dynamic and membrane-bound multi-protein assembly, named the replication complex (RC). The RC is composed of both viral and host-cell proteins that assemble within vesicles composed of the endoplasmic reticulum membrane, near the nucleus. At the heart of the flavivirus RC lies NS4B, a viral integral membrane protein that plays a role in virulence and in down-regulating the innate immune response. NS4B binds to the NS2B-NS3 protease-helicase, which itself interacts with the NS5 methyl-transferase polymerase. We present an overview of recent structural and functional data that augment our understanding of how viral RNA is replicated by dengue virus. We focus on structural data that illuminate the various roles played by proteins NS2B-NS3, NS4B and NS5. By participating in viral RNA cap methylation, the NS5 methyltransferase enables the virus to escape the host cell innate immune response. We present the molecular basis for this activity. We summarize what we know about the network of interactions established by NS2B-NS3, NS4B and NS5 (their “interactome”). This leads to a working model that is captured in the form of a rather naïve “cartoon”, which we hope will be refined towards an atomic model in the near future.

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Acknowledgements

This work was supported by grant NRF2016NRF-CRP001-063 to the laboratory of JL. We acknowledge the contributions of many coworkers (some now PIs active in the field) whose names are listed in the references. We also apologize for omitting some relevant primary litterature due to space limitations.

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Author notes

  1. Siew Pheng Lim

    Present address: Denka Life Innovation Pte Ltd., Singapore, Singapore

Authors and Affiliations

  1. Nanyang Institute of Structural Biology, Singapore, Singapore

    Julien Lescar, Sherryl Soh & Le Tian Lee

  2. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore

    Julien Lescar

  3. Novartis Institute for Tropical Diseases, Singapore, Singapore

    Sherryl Soh & Siew Pheng Lim

  4. Emerging Infectious Diseases Program, Duke-NUS Medical School Singapore, Singapore, Singapore

    Subhash G. Vasudevan

  5. Experimental Therapeutics Center, Singapore, Singapore

    Congbao Kang

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  1. Julien Lescar
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Editors and Affiliations

  1. Institute of Biochemistry, University of Lübeck, Lübeck, Germany

    Rolf Hilgenfeld

  2. Emerging Infectious Diseases Program, Duke-NUS Medical School Singapore, Singapore, Singapore

    Subhash G. Vasudevan

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Lescar, J., Soh, S., Lee, L.T., Vasudevan, S.G., Kang, C., Lim, S.P. (2018). The Dengue Virus Replication Complex: From RNA Replication to Protein-Protein Interactions to Evasion of Innate Immunity. In: Hilgenfeld, R., Vasudevan, S. (eds) Dengue and Zika: Control and Antiviral Treatment Strategies. Advances in Experimental Medicine and Biology, vol 1062. Springer, Singapore. https://doi.org/10.1007/978-981-10-8727-1_9

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