PerspectiveMolecular Biology

Viruses hijack a host lncRNA to replicate

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Science  24 Nov 2017:
Vol. 358, Issue 6366, pp. 993-994
DOI: 10.1126/science.aar2300

Viruses are parasitic entities that lack the basic metabolic machinery required to provide the energy and biosynthetic building blocks needed for their replication. To overcome this obstacle, viruses hijack the cellular metabolic machinery of their hosts in order to complete their life cycle and propagate. Yet, how viruses rewire cellular metabolic pathways remains poorly understood. On page 1051 of this issue, Wang et al. (1) identify a long noncoding RNA (lncRNA) called lncRNA-ACOD1 that is potently induced by multiple viruses, including vesicular stomatitis virus, vaccinia virus, and herpes simplex virus 1, in several mouse tissues, as well as by influenza virus in several human cell lines. This lncRNA promotes viral replication through the activation of the metabolic enzyme glutamic-oxaloacetic transaminase 2 (GOT2). Importantly, as enhancement of GOT2 activity by lncRNA-ACOD1 is required for optimal viral replication, mouse and human cells are dramatically protected from infection by simply down-regulating the amounts of this single lncRNA. Thus, this work uncovers a critical evolutionarily conserved mechanism by which viruses co-opt cellular metabolism for their own benefit. Moreover, it unveils a previously uncharacterized function of lncRNAs that could potentially be exploited for the development of new antiviral therapeutics.

Viruses rewire cell metabolism through a host lncRNA

lncRNA-ACOD1 is induced following viral infection to boost the activity of the metabolic enzyme GOT2 in order to increase the production of key metabolites required for viral replication.

GRAPHIC: K. SUTLIFF/SCIENCE

Viruses have evolved to regulate many host pathways to promote their own replication, and host metabolism is no exception: Upon infection, most viruses potently induce aerobic glycolysis, fatty acid synthesis, and glutaminolysis (2). By promoting these carbon source utilization pathways, viruses mobilize energy and cellular substrates for their own replication and virion production, as well as to promote the survival of the infected host cell (2). Nevertheless, the mechanisms by which viruses rewire host metabolism for their own benefit are largely unknown. Recently, multiple metabolic enzymes have been described to bind RNA, including lncRNAs (3). For example, the metabolic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been described to “moonlight” and perform secondary function in the regulation of inflammatory mRNA translation (4). Whether the converse is true, and RNAs bound to host enzymes regulate their catalytic activity to control cellular metabolism at steady state or in the context of viral infection, is an exciting direction of inquiry.

In the past decade, lncRNAs have emerged as key regulators of gene expression programs in diverse biological contexts and cell types. In particular, lncRNAs have been shown to control fundamental biological processes such as organism segmentation, X-chromosome inactivation, parental imprinting, and cellular survival though epigenetic and transcriptional regulation of gene expression in the nucleus (58). Yet, whether lncRNAs control cellular metabolic pathways directly in the cytoplasm is largely unknown. Wang et al. now show that through nuclear factor κB (NF-κB) activation, RNA and DNA viruses induce the expression of lncRNA-ACOD1, a cytoplasmic lncRNA that reshapes the cellular metabolic environment to promote viral replication. lncRNA-ACOD1 alters host metabolism by directly regulating the activity of GOT2, which is critical for the metabolism of the amino acid glutamine. As such, this study paves the way for a new paradigm of lncRNA function: lncRNA allosteric regulation of metabolic enzymes. Moreover, as lncRNA-ACOD1 is induced by viruses independently of type I interferon, a key host defense pathway triggered by viral infection, these results indicate that this previously unknown lncRNA regulatory mechanism can be exploited by viral pathogens.

GOT2 is primarily located in mitochondria, where it converts by-products of the amino acid glutamine into aspartate and a-ketoglutarate (αKG). These metabolites in turn can replenish intermediates of the tricarboxylic acid cycle—a key metabolic pathway—or be shuttled into the cytoplasm to support adenosine 5′-triphosphate (ATP) production through glycolysis (the glucose metabolism pathway) (9). Allosteric activators often bind to noncatalytic sites of enzymes to induce conformational changes that enhance their affinity for their cognate substrates (10). Wang et al. show that viral infection induces the translocation of GOT2 to the cytoplasm, where it directly interacts with lncRNA-ACOD1 through a 15–amino acid motif localized in close proximity to the substrate site of this enzyme. More importantly, the authors show that this interaction increases the production of aspartate and αKG by GOT2 and that these metabolites directly promote viral replication in vitro and in vivo in live animals. As the GOT2 motif and the interacting sequence of this lncRNA are well conserved across species, it is possible that this represents a primordial mechanism that evolved to boost the production of ATP to cope with metabolic stress by directly increasing the affinity of GOT2 for its substrates in the cytoplasm.

Although the findings of Wang et al. have uncovered a new function for lncRNAs and an unexpected form of host-pathogen interaction, several questions remain. For example, it is unclear what the evolutionarily conserved role is for lncRNA-ACOD1–mediated regulation of GOT2 enzymatic activity. Although this process is co-opted by viruses to promote their replication, lncRNA-ACOD1 and GOT2 are constitutively expressed in tissues such as the heart, indicating that activation of this enzyme by this lncRNA could have important physiological functions beyond viral replication. It is also unclear what the prevalence is of lncRNAs that are hijacked by viruses to enhance their replication cycle. lncRNA-ACOD1 represents the first example of a host lncRNA that is co-opted by viruses to modulate cellular metabolism for their advantage. Of note, Wang et al. find that several other lncRNAs are potently induced by viruses independently of those triggered by host antiviral responses, suggesting that these molecules may also augment viral infection. Further, emerging evidence indicates that RNA binding to metabolic enzymes is a pervasive phenomenon. The allosteric activation of GOT2 catalytic activity by the lncRNA-ACOD1 is an example of how critical and well-conserved these interactions might be. Thus, it is plausible to speculate that this study is just the tip of the iceberg, and that key roles for lncRNAs in the regulation of metabolic enzymes might be uncovered in the near future.

References and Notes

  1. Acknowledgments: J.H.-M. was supported by NIH (R21AI128060, R21DK111755, and R01HL136572) and the Pew Charitable Trust; J.J.K. by NIH (F30HL138739-01A1); and W.K.M. by NIH (F31AI124538).
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