Viral Evasion and Manipulation of Host RNA Quality Control Pathways

Abstract

Viruses have evolved diverse strategies to maximize the functional and coding capacities of their genetic material. Individual viral RNAs are often used as substrates for both replication and translation and can contain multiple, sometimes overlapping open reading frames. Further, viral RNAs engage in a wide variety of interactions with both host and viral proteins to modify the activities of important cellular factors and direct their own trafficking, packaging, localization, stability, and translation. However, adaptations increasing the information density of small viral genomes can have unintended consequences. In particular, viral RNAs have developed features that mark them as potential targets of host RNA quality control pathways. This minireview focuses on ways in which viral RNAs run afoul of the cellular mRNA quality control and decay machinery, as well as on strategies developed by viruses to circumvent or exploit cellular mRNA surveillance.

FIG 1

Execution and evasion of host nuclear RNA decay. (Left) RNAs that are not efficiently exported from the nucleus (e.g., due to intron retention) undergo hyperadenylation and exosome-mediated decay. (Right) Viral RNAs can escape degradation by physically blocking access to the transcript 3′ end with specialized RNA structures such as the KSHV PAN ENE or by promoting export of unspliced or partially spliced mRNA. Red RNA segments indicate intronic sequences.

FIG 2

Determinants of cellular and viral RNA susceptibility to NMD. (Left) RNA features leading to induction of NMD. In each case, translation termination occurs at sites distant from the 3′ end of the transcript. Decay is accelerated if termination takes place upstream of an EJC. (Right) RSV full-length mRNAs use the RSE to recruit host PTBP1 protein to the vicinity of the gag stop codon, preventing UPF1 association and inhibiting NMD. If the RSE is deleted or unable to bind PTBP1, RSV mRNAs are efficiently degraded by NMD. Positions of TCs typically used in full-length RNAs are indicated by stop signs, and positions of start and stop codons of additional ORFs are shown with light gray and red vertical lines, respectively. Red segments of RNAs indicate regions that may be recognized by UPF1 as aberrantly long 3′UTRs. LTR, long terminal repeat.

FIG 3

Scenarios for NMD modulation by translational recoding events. Readthrough (RT) or frameshifting (FS) can protect transcripts from NMD, if the downstream TC is in a position not sensed by NMD (top [first] mRNA). This activity can be antagonized by increasing the length of the downstream ORF (second mRNA) or abolished if the downstream TC is itself followed by a long 3′UTR (third mRNA). In contrast, frameshifting events that cause usage of an upstream TC can induce decay (bottom mRNA). Hypothetical RNA lengths shown are for illustrative purposes only; lightly shaded stop signs indicate TCs that are not used constitutively. nt, nucleotide.