XRN1is a Species-Specific Virus Restriction Factor in Yeasts

Abstract

In eukaryotes, the degradation of cellular mRNAs is accomplished by Xrn1 and the cytoplasmic exosome. Because viral RNAs often lack canonical caps or poly-A tails, they can also be vulnerable to degradation by these host exonucleases. Yeast lack sophisticated mechanisms of innate and adaptive immunity, but do use RNA degradation as an antiviral defense mechanism. We find a highly refined, species-specific relationship between Xrn1p and the "L-A" totiviruses of different Saccharomyces yeast species. We show that the gene XRN1 has evolved rapidly under positive natural selection in Saccharomyces yeast, resulting in high levels of Xrn1p protein sequence divergence from one yeast species to the next. We also show that these sequence differences translate to differential interactions with the L-A virus, where Xrn1p from S. cerevisiae is most efficient at controlling the L-A virus that chronically infects S. cerevisiae, and Xrn1p from S. kudriavzevii is most efficient at controlling the L-A-like virus that we have discovered within S. kudriavzevii. All Xrn1p orthologs are equivalent in their interaction with another virus-like parasite, the Ty1 retrotransposon. Thus, Xrn1p appears to co-evolve with totiviruses to maintain its potent antiviral activity and limit viral propagation in Saccharomyces yeasts. We demonstrate that Xrn1p physically interacts with the Gag protein encoded by the L-A virus, suggesting a host-virus interaction that is more complicated than just Xrn1p-mediated nucleolytic digestion of viral RNAs. Author SummaryLike other eukaryotes, Saccharomyces cerevisiae is chronically infected with viruses. It is fascinating to consider how S. cerevisiae deals with viral infection, because yeast have limited mechanisms of immunity. Our paper focuses on Xrn1p, an enzyme that is important for the destruction of irregular cellular RNAs in all eukaryotic cells. Xrn1p also degrades viral RNAs, owing to the fact that viral RNAs share biochemical characteristics with aberrant cellular mRNAs. Xrn1p was previously known to efficiently control the replication of a S. cerevisiae virus called "L-A. " We find that two different L-A viruses of Saccharomyces yeasts are best controlled by the Xrn1p from their own host species compared to the PLOS Pathogens |

The frenemies within: viruses, retrotransposons and plasmids that naturally infectSaccharomycesyeasts

“…Instead, the antiviral activity of Xrn1p from each Saccharomyces species may have evolved to control the replication of their resident totiviruses in a species‐specific manner. This is supported by the observation that Xrn1p from S. kudriavzevii is best at inhibiting a totivirus from S. kudriavzevii (Rowley et al , ). Importantly, the housekeeping functions of Xrn1p have been conserved over evolutionary time, as XRN1 from different Saccharomyces species and Mus musculus (mouse) can complement the XRN1 gene from S. cerevisiae (Bashkirov et al ., ; Rowley et al ., ) .…”

“…In S. cerevisiae , there are many examples of genetic and molecular methods that could be leveraged to understand the effect of viral parasitism on host physiology and evolution. For example, yeast can be easily modified to express host proteins from different Saccharomyces species to test the effect of evolution on the replication of yeast nucleic acid elements (Rowley et al , ). Specifically, genome‐wide gene deletion screens have been effectively used to identify hundreds of genes and cellular processes that are involved in Ty retrotransposon replication (including, but not limited to, nucleocytoplasmic transport, DNA repair, chromatin organization, transcription regulation, P‐bodies etc.)…”

“…Totiviruses and narnaviruses synthesize RNAs that lack a 5′ cap structure, and have evolved mechanisms to protect their RNAs from Xrn1p‐mediated degradation (Esteban et al , ; Fujimura and Esteban, ; Fujimura and Esteban, ; Fujimura and Esteban, ). Evolutionary analysis of the XRN1 gene in Saccharomyces yeasts has found that it is evolving rapidly, potentially because of its antagonistic relationship with yeast viruses (Rowley et al , ). Indeed, when the XRN1 gene from S. cerevisiae is replaced with XRN1 from a different Saccharomyces species, the antiviral activity against a S. cerevisiae totivirus is greatly diminished (Rowley et al , ).…”

“…Evolutionary analysis of the XRN1 gene in Saccharomyces yeasts has found that it is evolving rapidly, potentially because of its antagonistic relationship with yeast viruses (Rowley et al , ). Indeed, when the XRN1 gene from S. cerevisiae is replaced with XRN1 from a different Saccharomyces species, the antiviral activity against a S. cerevisiae totivirus is greatly diminished (Rowley et al , ). This would suggest that XRN1 within S. cerevisiae has evolved specifically to target its resident totivirus.…”

“…Putative totiviruses have been identified within Saccharomyces yeasts by the detection of viral genomic dsRNAs (Naumov et al , ). The genomic sequence of several totiviruses from Saccharomyces yeasts have also been determined, including S. cerevisiae virus L‐A (ScV‐L‐A), ScV‐L‐A28, ScV‐L‐A‐lus (Diamond et al , ; Konovalovas et al , ; Park et al , ; Rodríguez‐Cousiño et al , ), S. cerevisiae virus L‐BC (ScV‐L‐BC) (Park et al , ) and Saccharomyces kudriavzevii virus L‐A1 (SkV‐L‐A1) (Rowley et al , ). The dsRNA viral genome of Saccharomyces totiviruses is monopartite, ~4600 base pairs in length and encodes the proteins Gag and Gag–pol (Icho and Wickner, ).…”