Virus Escape and Manipulation of Cellular Nonsense-Mediated mRNA Decay

Figures

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  Figure 1. Different types of cellular mRNAs that can be substrates for nonsense-mediated mRNA decay (NMD). (A) An mRNA with a normal termination codon (TC) positioned in a context that does not trigger NMD: the termination codon is at the end of the last exon followed by a short 3’‑untranslated region (3’-UTR). (B–F) NMD targets comprise mRNAs with a truncated ORF due to a premature termination codon (PTC) in an internal (B) or terminal (C) exon. The presence of protein complexes known as exon junction complexes (EJCs) downstream the TC increases, but it is not necessary for, NMD (see Section 3). Upstream ORF (uORF), (D), the presence of EJC-associated introns in the 3’-UTR (E), and long 3’-UTR (F), all act as RNA destabilizing factors and trigger NMD. White boxes denote translated ORFs; gray boxes denote the fraction of the ORF that is not translated due to the presence of a PTC. Ribosomes are indicated in black, EJC in purple.

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  Figure 2. Different types of viral mRNAs that can be substrates for NMD. Similar to aberrant or unconventional cellular mRNA, viral transcripts contain features that make them susceptible to NMD, including the presence of PTC and long 3’-UTRs (A); the absence of cap-structure and polyA (B); uORFs (C); and a combination of all such as in the case of retroviruses RNAs, the translation of which also includes ribosomal frameshifts (D). In the case of Rous sarcoma virus (RSV), RNA secondary structures immediately downstream of the TC can act as RNA Stability Elements (RSE; D).

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  Figure 3. The replication cycle of a positive-stranded RNA ((+)RNA virus). (A) The bi-cystronic mRNA genome of Alphaviruses is capped a poly-adenylated. The first ORF encodes the replicase proteins; the second ORF encodes the structural genes (capsid and envelope proteins). (B) After virus entry, the genome is delivered into the cytoplasm where the first ORF is translated, leaving a ≈4000 nucleotides long 3’-UTR. (C) Newly synthesized viral replicase polyproteins assemble at the 3’-end of the genome and produce a complementary “minus” sense copy. Translation of the viral genome must be shut down. (D) After auto-proteolytic cleavage, the replicase complex switches the template and uses the “minus” strand to synthetize new copies of full-length genome and a shorter sub-genomic mRNA that encodes the structural proteins (the second ORF).