Viral Nucleases Induce an mRNA Degradation-Transcription Feedback Loop in Mammalian Cells

Abstract

Gamma-herpesviruses encode a cytoplasmic mRNA-targeting endonuclease, SOX, that cleaves most cellular mRNAs. Cleaved fragments are subsequently degraded by the cellular 5′-3′ mRNA exonuclease Xrn1, thereby suppressing cellular gene expression and facilitating viral evasion of host defenses. We reveal that mammalian cells respond to this widespread cytoplasmic mRNA decay by altering RNA polymerase II (RNAPII) transcription in the nucleus. Measuring RNAPII recruitment to promoters and nascent mRNA synthesis revealed that the majority of affected genes are transcriptionally repressed in SOX-expressing cells. The transcriptional feedback does not occur in response to the initial viral endonuclease-induced cleavage, but instead to degradation of the cleaved fragments by cellular exonucleases. In particular, Xrn1 catalytic activity is required for transcriptional repression. Notably, viral mRNA transcription escapes decay-induced repression, and this escape requires Xrn1. Collectively, these results indicate that mRNA decay rates impact transcription, and that gamma-herpesviruses use this feedback mechanism to facilitate viral gene expression.

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

“…Studying these 'escapees' in aggregate is complicated, however, by the fact that multiple mechanisms can promote apparent escape. These include lack of a targeting motif, indirect transcriptional effects, and active evasion of cleavage [22,[24][25][26][27][28]. This latter phenotype, termed dominant escape, is particularly notable as it involves a specific RNA element whose presence in the 3' UTR of an mRNA protects against SOX cleavage, regardless of whether the RNA contains a targeting motif.…”

Do You Believe in ReincaRNAtion? Herpesviruses Reveal Connection between RNA Decay and Synthesis

“…Reciprocally, if transcription is slowed due to mutations in Pol II, mRNA turnover is also slowed. Based on the results reported by Abernathy et al (2015), mammalian cells demonstrate clear interconnections between RNA synthesis and decay but do not use a similar buffering mechanism. In fact, transcription is decreased upon stimulation of Xrn1 activity resulting from SOX-mediated RNA cleavage, while Xrn1 knockdown alone showed no effects on transcription in the cells tested.…”

“…Personally, we've always found the last course of action to be the most effective. Recent studies by Abernathy et al (2015), presented in this issue, indicate that cells also prefer this third course of action.…”

“…In addition to viral mRNAs being refractory to the SOX/Xrn1-mediated transcriptional feedback described by Abernathy et al (2015), global analyses indicated that not all cellular mRNAs are affected as well. Using Gene Ontology (GO) analysis, the authors observed no clear link among the genes that are selectively silenced by this mechanism.…”

Interplay between Transcription and RNA Degradation

“…Interestingly, a functional coupling between the transcription and degradation was exploited by herpes virus [30]. Gamma-herpesviruses encode a cytoplasmic endonuclease, SOX, which cleaves cellular mRNAs.…”