Viral subversion of nonsense-mediated mRNA decay

Abstract

Viruses have evolved in tandem with the organisms that they infect. Afflictions of the plant and animal kingdoms with viral infections have forced the host organism to evolve new or exploit existing systems to develop the countermeasures needed to offset viral insults. As one example, nonsense-mediated mRNA decay, a cellular quality-control mechanism ensuring the translational fidelity of mRNA transcripts, has been used to restrict virus replication in both plants and animals. In response, viruses have developed a slew of means to disrupt or become insensitive to NMD, providing researchers with potential new reagents that can be used to more fully understand NMD mechanism. NONSENSE-MEDIATED mRNA DECAY IN PLANTS AND ANIMALS: AN OVERVIEWThe replication of genes during cell division, as well as gene expression (i.e. the synthesis of precursor-mRNAs, or pre-mRNAs, and the subsequent processing of pre-mRNAs to mRNAs), routinely results in low albeit detectable levels of mutations that can be deleterious. Before these mutations are etched into what is often the final effector of gene function, namely protein, it behooves the organism to eliminate them. As such, the cell has put in place quality-control systems to inspect and eliminate mRNAs that could affect fitness (Wolin and Maquat 2019). Nonsense-mediated mRNA decay (NMD) is one such Cold Spring Harbor Laboratory Press on May 4, 2021 -Published by rnajournal.cshlp.org Downloaded fromsystem. NMD eliminates transcripts that harbor a premature termination codon (PTC) and thereby could give rise to a truncated, non-functional or even toxic protein.In mammalian cells, NMD involves proteins coordinately attaching to, remodeling, and moving on RNAs. The machinery necessary for recognition of some NMD substrates is deposited during the process of gene transcription within nuclei, as reviewed extensively by Kurosaki and co-workers (Kurosaki et al. 2019) (Fig 1). For genes producing pre-mRNAs that undergo splicing, the act of splicing deposits a set of factors termed the exon-junction complex (EJC) at sites ~2024-nucleotides upstream of exonexon junctions, marking these locations. The nuclear EJC, composed of eukaryotic initiation factor 4A3 (eIF4A3), which is a helicase that anchors the EJC to the RNA, RNA-binding protein 8A (RBM8A; the mammalian homologue of Y14) and the protein mago nashi homolog (MAGOH), is further decorated with accessory factors and is maintained on spliced mRNAs during their export to the cytoplasm. There, mRNAs are initially translated while in complex with the capbinding complex (CBC), composed of cap-binding protein 80 (CBP80) and CBP20. Most termination codons are normally located in the final exon of mRNAs. However, should a ribosome terminate >5055-nucleotides upstream of an exonexon junction whose generation by splicing resulted in the deposition of an EJC, the ribosome will be unable to physically remove that EJC. Such termination events, which often occur at a PTC, allow eukaryotic release factor 1 (eRF1) and eRF3 to recruit the central NM...

Functional interactomes of the Ebola virus polymerase identified by proximity proteomics in the context of viral replication

“…We selected TurboID, an engineered promiscuous biotin ligase that is optimized for biotinylation of exposed lysine residues on proteins within a ~10 nm radius (Branon et al, 2018). Since the EBOV polymerase (EBOV_pol) requires both L and VP35 proteins to function, we used the split-TurboID system, which was engineered from full-length TurboID to produce two inactive fragments (Cho et al, 2020), sN-and sC-TurboID, that when brought together via protein-protein interactions, reconstitute full-length TurboID and its biotin ligase activity. To construct EBOV L-sNTurboID, we inserted sNTurboID into a predicted flexible loop region in EBOV L, a site that can tolerate insertion of mCherry (Hoenen et al, 2012).…”

“…Here we discovered two critical players in the cellular nonsense-mediated decay (NMD) pathway, UPF1 and GSPT1, which can both regulate EBOV infection. Although the role of NMD decay in virus infection has been examined for positive-strand and double-strand RNA viruses, retroviruses and influenza (Balistreri et al, 2017;Declercq et al, 2020;Popp et al, 2020;Tran et al, 2021), how NMD affects negative-strand RNA viruses like EBOV that replicate in the cytoplasm remains unclear. In the cellular NMD pathway, UPF1 degrades aberrant mRNAs by binding to the translation-termination complex (GSPT1/eRF3-eRF1) upon ribosomal recognition of a premature termination codon (PTC) in the mRNA (Kurosaki and Maquat, 2016).…”

“…This process is typically coupled with translation termination and promoted by the interaction between UPF1 and the termination complex (GSPT1/eRF3-eRF1) (Kurosaki et al, 2019). The NMD pathway has been shown to restrict multiple positive- and double-strand RNA viruses, but not retroviruses or influenza virus (Ajamian et al, 2008b; Balistreri et al, 2017; Declercq et al, 2020; Popp et al, 2020; Tran et al, 2021). How NMD affects negative-strand RNA viruses like EBOV that replicate in the cytoplasm remains to be determined.…”

Unusual SMG suspects recruit degradation enzymes in nonsense‐mediated mRNA decay

“…[41] Thus, viral proteins that inhibit NMD mechanisms are likely to benefit viral replication. This hypothesis has received experimental evidence from studies done, for example, on human and animal coronaviruses, hepatitis C virus, West Nile, Dengue, Semliki Forest, Zika or human Tlymphotrophic type 1, viruses (reviewed in [1][2][3]).…”

Elucidation of the Mechanism of Host NMD Suppression by HTLV-1 Rex: Dissection of Rex to Identify the NMD Inhibitory Domain

“…It has been widely reported that viral RNA is a target of NMD, and RNA viruses have evolved their own strategies to protect viral RNA from NMD [28][29][30][31]. HTLV-1 encodes more than 10 different viral proteins within its 9 kbp proviral genome.…”