Molecular Interaction of Nonsense-Mediated mRNA Decay with Viruses

Figures

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  Figure 1. PTC-based NMD activation and RNA decay. When PTC is located >50-55 nucleotides upstream of the exon–exon junction. EJC deposits 20–24 nucleotides upstream of the exon–exon junction and cannot be removed by translating ribosomes. Subsequent deposition of eRF1 and eRF2 dissociates ribosome, thereby binding eRF3 and UPF1. SMG1-mediated phosphorylation of UPF1 initiates a conformational change of UPF1 to recruit UPF2 and UPF3, which precedes the reaction further. SMG1, UPF1, eRF1, and eRF3 together form the SURF complex. Afterward, UPF2 connects EJC and UPF1 via UPF3, which recruits relevant decay factors. Target transcripts can be degraded by two major cellular cleavage pathways, endo-nucleolytic and exo-nucleolytic. SMG6 is an endonuclease recruited by phosphorylated UPF1 at the PTC, cleaving the NMD substrate. SMG5/7 promote the exo-nucleolytic pathway by recruiting decapping complex DCP1a/DCP2 at the 5′ end and recruiting deadenylation complex CCR4-NOT at the 3′ end. Nascent decapped transcripts were further digested in a 5′→3′ manner via XRN1*. Deadenylated RNA transcripts can be degraded in two ways: exosome-mediated digestion in a 3′→5′ manner and XRN1*-mediated digestion in a…

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  Figure 2. Schematic diagram of various viral RNAs targeted by host NMD. (a) Positive sense RNA virus possesses two or more separated open reading frames (e.g., semliki forest virus and sindbis virus) or a long 3′ UTR (e.g., pea enation mosaic virus 2); (b) Retroviral RNA (e.g., HIV, Rous Sarcoma Virus) harboring internal termination codons (iTC) in the gag gene; (c) Susceptible RNAs of DNA viruses (e.g., Kaposi’s sarcoma-associated herpesvirus, Epstein-Barr virus) with an extended 3′ UTR and introns [SGP: Sub-Genomic Promoter].

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  Figure 3. Viral protein-based strategies to modulate NMD activity: (1) Retroviral Tax factor antagonizes NMD by binding with eRF3 and UPF1 to prevent the SURF complex formation. By binding with UPF1, Tax disrupts its translocation and binding affinity to nucleic acids and other proteins; (2) HCV Core Protein disrupts NMD by binding with host protein WIBG to block the recycling interaction between WIBG and MAGOH/Y14; (3) Trans-acting activator (TAV) of CaMV interrupts decapping by interacting with VCS and subsequent decay of decapped transcripts by the XRN complex; (4) Coronavirus N-protein binds to UPF1 and diminishes its activity for NMD; (5) SFV replicase protein dislocates UPF1 from viral RNA to modulate host NMD response; (6) Non-structural protein (NSP5) promotes UPF1 degradation during rotavirus infection to inhibit the RNA decay pathway.