Research Article: Cytoplasmic Viruses: Rage against the (Cellular RNA Decay) Machine

Date Published: December 5, 2013

Publisher: Public Library of Science

Author(s): Stephanie L. Moon, Jeffrey Wilusz, Vincent Racaniello.

http://doi.org/10.1371/journal.ppat.1003762

Abstract

Partial Text

As our appreciation increases for the pervasive nature of transcription in the cell, so too has our appreciation for the major role of RNA decay/stability in regulating both the quantity and the quality of gene expression. As soon as viral RNAs appear in the cell, they must be prepared to combat or avoid cellular RNA decay pathways. This review describes the myriad ways that viruses deal with the general host RNA decay machinery that is active in the cell immediately upon viral infection—turning what, at first, appears to be very hostile territory for a foreign transcript into a sort of “promised land” for viral gene expression. It is interesting to note that cells likely try to adapt to this viral interference with the general RNA decay machinery by inducing a variety of novel RNases as part of a molecular arms race.

The cellular RNA decay machinery constantly monitors transcripts, from the time they are synthesized in the nucleus until the end of their lifespan in the cytoplasm. Aberrant products of transcription initiation (e.g. PROMPTS), capping, and termination are quickly degraded by nuclear RNA quality control surveillance complexes. Misfolded, “mis”-translated (e.g. mRNAs with a premature termination codon), and mispackaged mRNAs are also quickly degraded in the cytoplasm. In addition to removing aberrant mRNAs, up to 50% of cellular gene expression may be controlled by changes in mRNA stability. When a typical cellular mRNA is targeted for decay, it initially undergoes deadenylation—the removal of the 3′ poly(A) tail. The mRNA is then subject to processive exonucleolytic degradation in either the 3′-5′ direction by the exosome or Dis3L2, or it is marked by the LSm1-7/Pat1 complex for decapping by Dcp1/2 and degraded in the 5′-3′ direction by Xrn1 [1].

Several cytoplasmic viruses directly repress key aspects of the cellular RNA decay machinery to promote viral RNA stability. Picornaviruses use an aggressive mechanism for suppression of host RNA decay factors. Xrn1, Dcp1, Dcp2, Pan3 (a deadenylase), and AUF1 (a factor that targets RNAs for decay) are rapidly degraded during poliovirus or human rhinovirus infections by viral proteases and/or the host cell proteasome [3], [4]. The importance of this suppression has recently been demonstrated through the negative effects that AUF1 has on picornavirus replication [5]. The dispersal of P-bodies (cytoplasmic aggregates of host RNA decay factors) in several viral infections is also evidence of disruption of cellular RNA decay activities [6]. Alternatively, arthropod-borne flaviviruses, including West Nile virus (WNV), generate a large amount of a short subgenomic RNA (sfRNA) by stalling the Xrn1 5′-3′ exoribonuclease on pseudoknot-like structures in the viral 3′ UTR [7], [8]. Interestingly, stalling of Xrn1 on the viral 3′ UTR also inactivates the enzyme, presumably due to its slow release from sfRNA [9]. The repression of Xrn1 by the generation of sfRNA is very important in a flavivirus infection. WNV variants that cannot effectively form sfRNA show defects in viral growth in certain cell types and reduced cytopathology [8], [10]. Disparate RNA viruses have, therefore, evolved unique mechanisms by which they disarm host RNA decay pathways by inactivating or proteolytically degrading important nucleases to promote productive viral infections.

It has been known for some time that members of the Arenaviridae, Bunyaviridae, and the nuclear Orthomyxoviridae families steal the 5′ capped ends of host mRNAs to incorporate this cis-acting stability element into their own transcripts [14]. Emerging evidence indicates that the 2′-O-methylation of cap structures is read by innate immune interferon stimulated genes (ISGs) as a way to differentiate host versus virus transcripts. Cap-stealing mechanisms used by segmented RNA viruses to generate their mRNAs circumvent this innate detection system. Furthermore, recent evidence indicates that cellular trans-acting factors that stabilize host transcripts are also purloined by thieving viral RNAs.

Virally encoded endonucleases are important for many aspects of viral replication, including the fine-tuning of viral gene expression by rapidly depleting old viral mRNAs to enhance the expression of newly transcribed mRNAs [20]. In addition, to make a cell more amenable to virus production, these virally encoded nucleases may also create a new “sandbox” in the cytoplasm for viral RNAs by initiating the large-scale decay of cellular mRNAs and dramatically altering the landscape of host gene expression. Interestingly, the internal cleavage of host mRNAs by disparate betacoronaviruses, influenza viruses, vaccinia viruses, and the nuclear herpesviruses may force host exoribonucleases like Xrn1 and the exosome to divert their attention to degrading this large number of products of viral endonucleolytic decay [21]. The host RNA decay machinery may, therefore, become saturated as endonucleolytic decay products rapidly accumulate during viral infection, limiting its normal functions. Thus, virus-derived nucleases may disrupt normal gene expression and RNA decay-related quality control mechanisms to help viral RNAs escape detection by the cellular RNA decay machinery.

Considering the importance of RNA stability in regulating transcript abundance, the inactivation or commandeering of cellular RNA decay factors by viruses is likely to significantly alter host gene expression. How might changes in host mRNA stability contribute to virus-induced pathology during infection (Figure 1)? One example of this phenomenon is that wild-type Kunjin virus was significantly more pathogenic in both tissue culture and mouse models of infection than a mutant virus incapable of forming sfRNA [7]. Inactivation of Xrn1 by Kunjin virus sfRNA likely causes the stabilization and increase in abundance of numerous short-lived host transcripts, including chemokines, cytokines, and cell cycle regulators [6]. Dysregulation of these factors by Xrn1 inhibition may lead to excessive inflammation, dysregulation of the immune response, and/or changes in cell growth. Recent work in yeast has demonstrated the ability of Xrn1 to enter the nucleus and influence transcription rates, thus acting as a link between RNA decay and transcription [22]. Excitingly, the authors found that the exonucleolytic activity of Xrn1 was also required for the coupling between transcription and mRNA decay. Could sfRNA-mediated inactivation of Xrn1 cause a defect in the coordination of RNA decay and transcription in the host? If so, this could dramatically alter host gene expression and directly influence pathogenesis.

Viral RNAs have evolved a wide variety of mechanisms to successfully interface with the host RNA decay machinery. In fact, some of the most important questions in this field have yet to be answered. What are the consequences of viral inactivation of decay factors like Xrn1 in terms of disease? Can viruses also influence host transcription by manipulating RNA decay pathways to short-circuit feedback regulatory mechanisms? How do virus-induced changes in RNA decay pathways interface with potential changes in innate immune responses?

 

Source:

http://doi.org/10.1371/journal.ppat.1003762

 

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