The structure and function of the rous sarcoma virus RNA stability element

Abstract

For simple retroviruses, such as the Rous sarcoma virus (RSV), post-transcriptional control elements regulate viral RNA splicing, export, stability, and packaging into virions. These RNA sequences interact with cellular host proteins to regulate and facilitate productive viral infections. One such element, known as the RSV stability element (RSE), is required for maintaining stability of the full-length unspliced RNA. This viral RNA serves as the mRNA for the Gag and Pol proteins and also as the genome packaged in progeny virions. When the RSE is deleted from the viral RNA, the unspliced RNA becomes unstable and is degraded in a Upf1-dependent manner. Current evidence suggests that the RSE inhibits recognition of the viral gag termination codon by the nonsense-mediated mRNA decay (NMD) pathway. We believe that the RSE acts as an insulator to NMD, thereby preventing at least one of the required functional steps that target an mRNA for degradation. Here, we discuss the history of the RSE and the current model of how the RSE is interacting with cellular NMD factors.

Organizing Principles of Mammalian Nonsense-Mediated mRNA Decay

“…If a specific sequence element in the 3′ UTR, called the RSV stability element (RSE), is deleted, the transcript half-life is shortened in a way that requires UPF1 and translation. The RSE contains significant secondary structure as well as a single-stranded region that may base pair with an element upstream of the poly(A) tail (191, 199). Such fold-back constructs that shorten the physical distance between the termination codon and poly(A) tail have proven resistance to NMD (37), and this may be the method whereby RSV mRNAs escape detection by NMD.…”

“…Such fold-back constructs that shorten the physical distance between the termination codon and poly(A) tail have proven resistance to NMD (37), and this may be the method whereby RSV mRNAs escape detection by NMD. Alternatively (but not mutually exclusively), the RSE may recruit unknown factors that directly inhibit NMD (199), or it may prevent UPF1 accumulation on the 3′ UTR (96). …”

UPF1 Is Crucial for the Infectivity of Human Immunodeficiency Virus Type 1 Progeny Virions

“…When this stability element is deleted, the unspliced RSV RNA decays, and this decay can be inhibited by dominant negative UPF1 (19). It has been pointed out that HIV-1 full-length RNA also contains features potentially recognized by UPF1 (18). However, in contrast to what has been reported for RSV, a recent study suggests that UPF1 unexpectedly stabilizes the unspliced HIV-1 RNA (20).…”

“…When translation termination factors encounter a stalled ribosome due to a premature stop codon, they recruit UPF1, which subsequently engages its binding partner (UPF2) and the rest of the machinery that initiates the degradation of the defective transcript (17). Notably, there is evidence that retroviruses protect their genomic RNA against the NMD pathway (18). In the case of Rous sarcoma virus (RSV), the region immediately downstream of the gag frame harbors a stability element that inhibits recognition of the normal gag termination codon by UPF1 and the NMD pathway (19).…”

Retroviral strategy to stabilize viral RNA

“…Some, but not all, mRNAs bearing features such as uORFs and long 3’ UTRs are NMD targets, both in mammals and in yeast. Unspliced (thus presumably lacking EJCs) retroviral mRNAs are also targets of NMD [6]. NMD has been shown to play regulatory roles in humans, Drosophila melanogaster , Caenorhabditis elegans , and Saccromyces cerevisiae [4], and can affect more than a quarter of all expressed mammalian genes [7,8].…”