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Review
. 2012 Aug;15(4):500-5.
doi: 10.1016/j.mib.2012.04.009. Epub 2012 May 23.

Inhibition and avoidance of mRNA degradation by RNA viruses

Stephanie L Moon  1 , Michael D Barnhart, Jeffrey Wilusz
Affiliations
Review

Inhibition and avoidance of mRNA degradation by RNA viruses

Stephanie L Moon et al. Curr Opin Microbiol. 2012 Aug.

Abstract

The cellular mRNA decay machinery plays a major role in regulating the quality and quantity of gene expression in cells. This machinery involves multiple enzymes and pathways that converge to promote the exonucleolytic decay of mRNAs. The transcripts made by RNA viruses are susceptible to degradation by this machinery and, in fact, can be actively targeted. Thus, to maintain gene expression and replication, RNA viruses have evolved a number of strategies to avoid and/or inactivate aspects of the cellular mRNA decay machinery. Recent work uncovering the mechanisms used by RNA viruses to maintain the stability of their transcripts is described below.

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Figures

Figure 1
Figure 1. The major enzymes and pathways of cellular mRNA decay
As indicated by the ‘Start Here’ sign, the majority of mRNA degradation in eukaryotic cells is initiated by poly(A) shortening. The four best characterized deadenylase enzymes (CCR4, CAF1, PAN2/3 and PARN) are shown. Following deadenylation, the body of the mRNA is then degraded by one of two exonuclease pathways (or both acting in concert). The exosome complex degrades mRNAs in a 3′-5′ direction (top panel). Exosome-mediated decay leaves a short RNA fragment with a 5′ cap that gets removed by the scavenger decapping activity DCPS. In the 5′-3′ decay pathway (bottom panel), the mRNA is first decapped by DCP2 or Nudt16 and then the body of the mRNA is degraded by the XRN1 exoribonuclease. Many of the components of the 5′-3′ decay pathway can often be found associated in a cytoplasmic granule referred to as the P-body.
Figure 2
Figure 2. Alternative and specialized pathways of mRNA decay
Two of the major routes of alternative mRNA decay are highlighted. First, decay can be initiated by endonucleolytic cleavage through the direct recruitment of endonucleases. These enzymes can interact directly with their target RNAs (e.g PMR1, RNase L), be recruited as part of the nonsense-mediated decay pathway (NMD) at a premature termination codon (Smg6 endonuclease), by stalled ribosomes in the ‘no-go’ decay pathway by recruitment of the Dom34-Hbs1 complex, or by miRNAs directing Ago ‘slicer’ proteins of the RISC complex to the transcript. Alternatively, the exosome can be recruited to the 3′ end of malformed RNAs such as those lacking a translation termination codon (non-stop decay) or onto transcripts with structured 3′ ends by poly(A) or poly(U) tailing.
Figure 3
Figure 3. Regulation of mRNA stability
The decay of mRNAs is a highly regulated process. It can be promoted by the interaction of destabilizing factors such as the TTP, AUF1 and KSRP proteins, or by miRNAs. These destabilizing factors can serve to attract deadenylases as shown in the figure, or by alternative mechanisms such as endonucleolytic cleavage. Alternatively, mRNAs can be selectively stabilized by the recruitment of specific proteins such as HuR or PCBP2 to their 3′ UTRs.
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