Regulators of Viral Frameshifting: More Than RNA Influences Translation Events

Abstract

Programmed ribosomal frameshifting (PRF) is a conserved translational recoding mechanism found in all branches of life and viruses. In bacteria, archaea, and eukaryotes PRF is used to downregulate protein production by inducing a premature termination of translation, which triggers messenger RNA (mRNA) decay. In viruses, PRF is used to drive the production of a new protein while downregulating the production of another protein, thus maintaining a stoichiometry optimal for productive infection. Traditionally, PRF motifs have been defined by the characteristics of two cis elements: a slippery heptanucleotide sequence followed by an RNA pseudoknot or stem-loop within the mRNA. Recently, additional cis and new trans elements have been identified that regulate PRF in both host and viral translation. These additional factors suggest PRF is an evolutionarily conserved process whose function and regulation we are just beginning to understand. Expected final online publication date for the Annual Review of Virology, Volume 7 is September 29, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Modulation of Viral Programmed Ribosomal Frameshifting and Stop Codon Readthrough by the Host Restriction Factor Shiftless

“…Mechanistic insights into –1 PRF are also being sought through studies of two highly efficient PRF signals whose activity requires the participation of trans -acting proteins ( Figure 1 ). In the cardioviruses encephalomyocarditis virus (EMCV) and Theiler’s murine encephalitis virus (TMEV), frameshifting within the 2B gene requires viral protein 2A [ 37 , 38 , 39 ], and in the arterivirus porcine reproductive and respiratory syndrome virus (PRRSV), production of the nsp2TF protein by frameshifting is mediated by a complex of the viral protein nsp1β and host poly[C] binding protein (PCPB) [ 40 , 41 , 42 ].…”

Coordination of -1 Programmed Ribosomal Frameshifting by Transcript and Nascent Chain Features Revealed by Deep Mutational Scanning

“…Viruses utilize ribosomal frameshifting to increase their genomic coding capacity and to regulate the stoichiometric ratios of viral protein synthesis. Some rely on these motifs to coordinate genomic replication, while others utilize PRF to regulate the production of the structural proteins that mediate assembly (Penn et al, 2020a). In some cases, the frameshift products are themselves virulence factors that antagonize the host interferon response (Hallengard et al, 2014; Rogers et al, 2020; Snyder et al, 2013; Taylor et al, 2016).…”

“…This finding has since been echoed by recent evidence suggesting cotranslational folding of nsp10 alters -1PRF during translation of SARS-CoV-2 genome (Bhatt et al, 2020). The efficiency of - 1PRF can also be modified in trans by a variety of host and viral proteins and nucleic acids (Penn et al, 2020a). Thus, the efficiency of ribosomal frameshifting can be modified by a wide variety of effectors that tune the rate of translation, the structural properties of the transcript, and/ or the conformation of the nascent chain.…”

Coordination of -1 programmed ribosomal frameshifting by transcript and nascent chain features revealed by deep mutational scanning

“…Viruses utilize ribosomal frameshifting to increase their genomic coding capacity and to regulate the stoichiometric ratios of viral protein synthesis. Some rely on these motifs to coordinate genomic replication, while others utilize PRF to regulate the production of the structural proteins that mediate assembly ( 2 ). In some cases, the frameshift products are themselves virulence factors that antagonize the host interferon response ( 3–6 ).…”

“…This finding has since been echoed by recent evidence suggesting cotranslational folding of nsp10 alters −1PRF during translation of SARS-CoV-2 genome ( 23 ). The efficiency of −1PRF can also be modified in trans by a variety of host and viral proteins and nucleic acids ( 2 ). Thus, the efficiency of ribosomal frameshifting can be modulated by a wide variety of effectors that tune the rate of translation, the structural properties of the transcript, and/ or the conformation of the nascent chain.…”