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  • Review Article
  • Published:

The dependence of viral RNA replication on co-opted host factors

Nature Reviews Microbiology volume 10, pages 137–149 (2012)Cite this article

Subjects

Key Points

  • Positive-strand RNA ((+)RNA) viruses are major pathogens of humans, animals and plants. These viruses actively reprogramme the host cell metabolism to support the infection process and to allow viruses to escape or suppress host defence mechanisms.

  • To facilitate RNA replication, (+)RNA viruses interact with numerous host molecules via protein–protein, RNA–protein and protein–lipid interactions. These interactions are crucial for the formation of viral replication organelles, which produce new viral RNA progeny in host cells.

  • All characterized (+)RNA viruses assemble viral replication complexes, containing both viral and host proteins, on intracellular membranes. The subverted host factors play crucial parts in all steps of (+)RNA virus replication. Therefore, host factors are key determinants of viral pathology as well as viral evolution.

  • As there can be ∼20,000–30,000 different proteins in a typical eukaryotic cell, identifying all the proteins that are subverted by a given (+)RNA virus is a daunting task. Genome-wide and global proteomics approaches have recently emerged as a powerful means to identify the host factors involved in (+)RNA virus replication.

  • An emerging theme from the genome-wide screens is that many of the host proteins subverted for (+)RNA virus replication are unique for a given virus. This suggests that (+)RNA viruses have evolved different ways to utilize host cell resources.

  • In spite of the diverse sets of host factors co-opted by various viruses, functional and mechanistic studies suggest that different host proteins provide similar functions during viral RNA replication.

  • Common host factors that are recruited by (+)RNA viruses for their replication include: RNA-binding proteins that facilitate viral RNA synthesis; proteins involved in membrane bending that contribute to the formation of membrane-bound replication complexes; lipid synthesis enzymes that affect lipid composition and have a role in making a favourable microenvironment for viral replication; and chaperones and prolyl isomerases that facilitate the proper folding and functions of viral replication proteins during assembly of the viral replication complexes.

Abstract

Positive-sense RNA ((+)RNA) viruses such as hepatitis C virus exploit host cells by subverting host proteins, remodelling subcellular membranes, co-opting and modulating protein and ribonucleoprotein complexes, and altering cellular metabolic pathways during infection. To facilitate RNA replication, (+)RNA viruses interact with numerous host molecules through protein–protein, RNA–protein and protein–lipid interactions. These interactions lead to the formation of viral replication complexes, which produce new viral RNA progeny in host cells. This Review presents the recent progress that has been made in understanding the role of co-opted host proteins and membranes during (+)RNA virus replication, and discusses common themes employed by different viruses.

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Figure 1: Schematic infection cycle of positive-sense RNA viruses.
Figure 2: Remodelling the cellular secretory pathway to support human poliovirus replication.
Figure 3: Structures of the flavivirus replication complexes.
Figure 4: Proposed remodelling of the endoplasmic reticulum-associated protein degradation tuning pathway during coronavirus replication.
Figure 5: Functions of host factors during tombusvirus replication in Saccharomyces cerevisiae.

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Acknowledgements

The authors thank D. Smith and members of the Nagy lab for discussion. The authors apologize to those colleagues whose research on the replication of (+)RNA viruses is not mentioned in this Review owing to space restrictions. This work was supported by the US National Institutes of Health, National Institute of Allergy and Infectious Diseases.

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  1. Department of Plant Pathology, University of Kentucky, 201F Plant Science Building, Lexington, 40546, Kentucky, USA

    Peter D. Nagy & Judit Pogany

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Correspondence to Peter D. Nagy.

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Glossary

Peroxisomes

Organelles that are found in virtually all eukaryotic cells and are involved in the catabolism of fatty acids, damino acids and polyamines. Peroxisomes are important for energy metabolism.

Genome-wide approaches

Studies based on high-throughput screens that include a systematic analysis of all or most of the genes encoded by the genome of a particular host organism.

RNA interference

(RNAi). A pathway that, in most eukaryotes, controls which genes are active and their relative activities. The pathway is induced by small interfering RNAs (siRNAs), which are small double-stranded RNAs. Using a library of siRNAs, the expression of each gene in a given cell line or organism can artificially be knocked down.

Proteomic approaches

Global approaches that involve all or most of the proteins encoded by the genome of the particular host.

Yeast two-hybrid screens

Screens looking for proteinprotein or proteinnucleic acid interactions in Saccharomyces cerevisiae cells. The target protein is screened for physical interaction against a library of full-length or truncated genes that are expressed from a plasmid.

Protein microarray

A microarray based on purified (host) proteins fixed to the chip surface. These arrays are used to identify proteinprotein or proteinnucleic acid interactions, substrates of proteins or targets of biologically active small molecules.

Cap-independent translation

A method of translation used by several positive-sense RNA viruses, in which the usual requirement for the interaction of host translation initiation factors with the 5-cap (a special tag bound to the 5 end of an mRNA molecule) is circumvented, and select host initiation factors are recruited by alternative means to participate in translation.

SNARE-like protein

One of a large superfamily of proteins with a primary role in vesicle fusion.

Geranylgeranylated cellular protein

A protein that has been modified post-translationally by the attachment of one or two 20carbon lipophilic geranylgeranyl isoprene units (from geranylgeranyl diphosphate) to a cysteine at the carboxyterminus of the protein. Geranylgeranylation is proposed to function as a membrane anchor for proteins.

Actomyosin

A protein complex composed of actin and myosin.

Viral replication organelles

Large cellular structures that contain many individual viral replication complexes.

Trans-Golgi network

A complex network of membranes and associated vesicles in the so-called trans-face of the Golgi, which is involved in sorting and shipping proteins to their intended destinations in the cell.

ER exit sites

Selected areas within the endoplasmic reticulum (ER) from which transport vesicles carrying newly synthesized proteins and lipids bud off for transport to the Golgi apparatus.

ERGIC

(Endoplasmic reticulumGolgi intermediate compartment). An organelle in eukaryotic cells that mediates trafficking between the ER and the Golgi, facilitating the sorting of cargo.

Autophagy

A tightly regulated catabolic process involving the degradation of cellular components through the lysosomal machinery.

Stress granule

A type of dense proteinRNA aggregation in the cytosol, not surrounded by membrane, that appears when the cell is under stress. Stress granules may store and protect RNAs from harmful conditions under stress, and they serve as decision points for untranslated mRNAs for further storage, degradation or translation re-initiation.

P-bodies

(Processing bodies). Distinct foci within the cytoplasm, consisting of enzymes involved in mRNA turnover.>

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Nagy, P., Pogany, J. The dependence of viral RNA replication on co-opted host factors. Nat Rev Microbiol 10, 137–149 (2012). https://doi.org/10.1038/nrmicro2692

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