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  • Review Article
  • Published:

Rewiring cellular networks by members of the Flaviviridae family

Nature Reviews Microbiology volume 16, pages 125–142 (2018)Cite this article

Subjects

Key Points

  • Flaviviruses and hepaciviruses share similarities in their fundamental replication mechanisms and strategies to manipulate the host cell, yet important differences exist, likely reflecting the use of distinct host cell pathways.

  • RNA replication of Flaviviridae family members occurs in tight association with endoplasmic reticulum-derived membranes, which are reorganized into viral replication organelles. Whereas the morphology and the architecture of these replication organelles are well defined, relatively little is known about the viral and cellular factors orchestrating their biogenesis.

  • Protein folding, modification and degradation are essential, tightly regulated cellular processes, and a number of common host factors and pathways that are involved in these processes appear to be exploited by both flaviviruses and hepaciviruses at different steps of their replication cycle. These include heat shock protein 70 (HSP70) network components, the unfolded protein response, the ubiquitin-dependent proteasome system and autophagy.

  • Accumulating evidence indicates that lipids and lipid metabolism fulfil essential roles in the life cycle of Flaviviridae viruses. They alter the lipid composition of cellular membranes, serving as scaffold for the assembly of the viral replicase by changing their biophysical properties, such as curvature, permeability and fluidity.

  • The identification of host cell pathways and factors commonly used by members of the Flaviviridae family might help in the development of broad-spectrum antiviral drugs that target multiple members of this family and/or other virus families.

  • As exemplified by members of the Flaviviridae family, the use of host cell pathways does not follow conventional phylogeny but, rather, reveals unexpected commonalities with distantly related viruses, raising the question of evolutionary relationships between these viruses.

Abstract

Members of the Flaviviridae virus family comprise a large group of enveloped viruses with a single-strand RNA genome of positive polarity. Several genera belong to this family, including the Hepacivirus genus, of which hepatitis C virus (HCV) is the prototype member, and the Flavivirus genus, which contains both dengue virus and Zika virus. Viruses of these genera differ in many respects, such as the mode of transmission or the course of infection, which is either predominantly persistent in the case of HCV or acutely self-limiting in the case of flaviviruses. Although the fundamental replication strategy of Flaviviridae members is similar, during the past few years, important differences have been discovered, including the way in which these viruses exploit cellular resources to facilitate viral propagation. These differences might be responsible, at least in part, for the various biological properties of these viruses, thus offering the possibility to learn from comparisons. In this Review, we discuss the current understanding of how Flaviviridae viruses manipulate and usurp cellular pathways in infected cells. Specifically, we focus on comparing strategies employed by flaviviruses with those employed by hepaciviruses, and we discuss the importance of these interactions in the context of viral replication and antiviral therapies.

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Figure 1: Flavivirus and Hepacivirus genome organization and membrane topology of mature viral proteins.
Figure 2: Three-dimensional structure and organization of Flavivirus and Hepacivirus replication organelles.
Figure 3: Cellular pathways co-opted by Flavivirus and Hepacivirus.
Figure 4: Cellular organelles co-opted by Flavivirus and Hepacivirus.

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Acknowledgements

The authors apologize to all colleagues whose work they could not cite due to space limitations. Research in the authors' laboratory is supported by the Deutsche Forschungsgemeinschaft (SFB 1129, TP 11; SFB/TRR 83, TP 13; SFB/TRR179, TP 9), the Federal Ministry for Education and Research (BMBF) 'ERA-Net for Applied Systems Biology' (ERASysAPP) (SysVirDrug, grant no. 031A602B) and the EU H2020 project 'ANTIVIRALS' (grant no. 642434), all to R.B. C.J.N. is supported by the European Molecular Biology Organization (EMBO) (ALTF 466–2016).

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Author notes

  1. Christopher J. Neufeldt, Mirko Cortese and Eliana G. Acosta: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, 69120, Germany

    Christopher J. Neufeldt, Mirko Cortese, Eliana G. Acosta & Ralf Bartenschlager

  2. German Center for Infection Research, Heidelberg Partner Site, Heidelberg, 69120, Germany

    Ralf Bartenschlager

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Contributions

C.J.N., M.C. and E.G.A. researched data for the article. C.J.N., M.C., E.G.A. and R.B. substantially contributed to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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PowerPoint slides

Glossary

Guillain–Barré syndrome

An acute neurological disease (usually reversible) resulting from autoimmune destruction of the peripheral nervous system that is frequently triggered by infection.

Microcephaly

A neurological condition of abnormal brain development that causes substantially smaller infant head circumferences relative to age-matched controls.

Tropism

Tissue specificity of a virus. Tropism is determined primarily by the presence of membrane receptors that can be exploited by the virus to gain access to host cells.

Internal ribosome entry site

(IRES). A folded RNA element capable of recruiting the small ribosomal subunit that also mediates cap-independent initiation of RNA translation. IRES elements require only a subset of the canonical translation initiation factors, which are determined by the specific type of IRES.

Polyprotein

A polypeptide composed of individual domains that are released both co-translationally and post-translationally by proteolytic cleavage to produce functionally distinct proteins.

Very-low-density lipoprotein

(VLDL). A liver-produced plasma lipoprotein particle ∼30–70 nm in diameter involved in cholesterol and triglyceride transport. Low-density lipoprotein and VLDL contain distinct sets of apolipoproteins.

Cyclophilin

Peptidyl-prolyl isomerases (PPIases) that catalyse the cis–trans isomerization of peptide bonds at proline residues and facilitate protein folding.

Oligosaccharyltransferase

(OST). A heteromeric transmembrane protein complex located in the endoplasmic reticulum lumen that catalyses the transfer of a pre-assembled oligosaccharide to selected asparagine residues within the consensus sequence Asn-X-Ser/Thr of nascent polypeptides.

Ubiquitin-dependent proteasome system

(UPS). A multicomponent system for regulated protein degradation. Proteins are marked for degradation by conjugation with the ubiquitin polypeptide through the concerted action of modular conjugation machinery. Ubiquitylated substrates are recognized, unfolded and degraded by a large multisubunit protease complex called the proteasome.

CRISPR–Cas9

A site-specific gene-editing system derived from a bacterial adaptive defence system that retains foreign DNA in the CRISPR gene locus. The system is composed of a guide RNA homologous to the target gene and the CRISPR–Cas9 nuclease. Sequence complementarity guides Cas9 to the specific region targeted for cleavage.

Bortezomib

A dipeptide boronic acid derivate that reversibly inhibits the chymotryptic activity of the proteasome. It was the first therapeutic proteasome inhibitor approved by the FDA for clinical use as an anticancer drug.

Restriction factors

Cellular factors that inhibit pathogen replication.

AKT1–mTOR

An intracellular signalling pathway that regulates several cellular processes, including cell proliferation and survival.

Exosomes

Small extracellular vesicles released directly from cells or upon fusion of multivesicular bodies with the plasma membrane.

Lipophagy

An autophagic pathway that selectively targets lipid droplets and mobilizes lipids to be used for energy production.

ER-phagy

An autophagic pathway that selectively sequesters and degrades portions of the endoplasmic reticulum.

Parkin

An E3 ubiquitin ligase that is involved in autophagic elimination of damaged mitochondria (mitophagy). Mutations in the parkin gene are linked to autosomal recessive juvenile Parkinson disease.

Sterol regulatory element-binding protein

(SREBP). A membrane-bound transcription factor that regulates the transcription of genes involved in fatty acids and cholesterol metabolism.

Microfilament

Also known as actin filaments; a component of the cytoskeleton. Microfilaments range from 7–9 nm in diameter and are composed of actin polymers. Microfilaments are involved in several cellular processes, including cytokinesis, cell movement, endocytosis and muscle contraction.

Septins

GTPases that assemble into repeated hetero-oligomers and polymerize into higher-order structures, such as rings or filaments. Septins are the fourth cytoskeletal component and take part in several cellular processes, such as cell division, migration and pathogen interactions.

Interferon regulatory factor 3

(IRF3). A transcription factor that mediates the expression of type 1 interferons and interferon-stimulated genes.

Dynamin 1-like protein

(DRP1). A GTPase of the dynamin superfamily that mediate mitochondrial outer membrane fission events.

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Neufeldt, C., Cortese, M., Acosta, E. et al. Rewiring cellular networks by members of the Flaviviridae family. Nat Rev Microbiol 16, 125–142 (2018). https://doi.org/10.1038/nrmicro.2017.170

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