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RNA degradation in antiviral immunity and autoimmunity.

Rigby RE, Rehwinkel J - Trends Immunol. (2015)

Bottom Line: Post-transcriptional control determines the fate of cellular RNA molecules.Recent findings have revealed a role for NMD in targeting viral RNA molecules, thereby restricting virus infection.Interestingly, NMD is also linked to immune responses at another level: mutations affecting the NMD or RNA exosome machineries cause chronic activation of defence programmes, resulting in autoimmune phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.

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Related in: MedlinePlus

Nonsense-mediated decay (NMD). NMD recognises premature translation termination codons (PTCs) and this requires translation. The mechanism of PTC definition differs between species and individual transcripts. Two major pathways are shown here. (A) One important mechanism of PTC recognition relies on a protein complex called the exon-junction complex (EJC) [9]. EJCs are deposited on mRNAs during splicing and mark exon-exon junctions. EJCs are transported together with the mRNA into the cytoplasm and are removed from the mRNA during translation [82–84]. Importantly, most mRNAs contain the stop codon in their last exon; therefore, no EJCs are left on the mRNA when translation termination occurs. However, if mRNAs have a PTC upstream of the last exon, one or multiple EJCs remain on the mRNA at the moment when translation terminates. This constellation is recognised by a number of proteins including the essential NMD effectors UPF1, UPF2, and UPF3/3X. UPF1 (red) interacts with proteins involved in translation termination, while UPF2 (orange) and UPF3/3X (yellow) associate with the EJC. If an EJC is present downstream from a terminating ribosome, the UPF proteins interact to form a complex, SMG proteins (olive) are recruited, and degradation of the mRNA is initiated (middle panel) [5–8]. (B) EJCs are not always required for NMD [5–8]. Efficient translation termination requires interactions between proteins bound to the mRNA poly(A) tail and release factors, which associate with ribosomes at stop codons. If termination occurs at a PTC, the distance to the 3′-end and poly(A) tail may be too large to accommodate this interaction (red cross) [25,85–87]. This in turn is presumed to result in delayed release of the ribosome from the mRNA, allowing for assembly of UPF proteins and recruitment of SMGs independently of an EJC.
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fig0005: Nonsense-mediated decay (NMD). NMD recognises premature translation termination codons (PTCs) and this requires translation. The mechanism of PTC definition differs between species and individual transcripts. Two major pathways are shown here. (A) One important mechanism of PTC recognition relies on a protein complex called the exon-junction complex (EJC) [9]. EJCs are deposited on mRNAs during splicing and mark exon-exon junctions. EJCs are transported together with the mRNA into the cytoplasm and are removed from the mRNA during translation [82–84]. Importantly, most mRNAs contain the stop codon in their last exon; therefore, no EJCs are left on the mRNA when translation termination occurs. However, if mRNAs have a PTC upstream of the last exon, one or multiple EJCs remain on the mRNA at the moment when translation terminates. This constellation is recognised by a number of proteins including the essential NMD effectors UPF1, UPF2, and UPF3/3X. UPF1 (red) interacts with proteins involved in translation termination, while UPF2 (orange) and UPF3/3X (yellow) associate with the EJC. If an EJC is present downstream from a terminating ribosome, the UPF proteins interact to form a complex, SMG proteins (olive) are recruited, and degradation of the mRNA is initiated (middle panel) [5–8]. (B) EJCs are not always required for NMD [5–8]. Efficient translation termination requires interactions between proteins bound to the mRNA poly(A) tail and release factors, which associate with ribosomes at stop codons. If termination occurs at a PTC, the distance to the 3′-end and poly(A) tail may be too large to accommodate this interaction (red cross) [25,85–87]. This in turn is presumed to result in delayed release of the ribosome from the mRNA, allowing for assembly of UPF proteins and recruitment of SMGs independently of an EJC.

Mentions: NMD is a highly conserved mRNA surveillance pathway and has been reviewed in detail elsewhere [5–8]. Here, we will discuss only the basic principles of NMD (Figure 1). NMD detects mRNAs harbouring premature translation termination codons (PTCs) and then targets these transcripts for degradation. PTCs can arise as a consequence of gene mutations or errors during transcription. If translated, PTC-containing mRNAs encode C-terminally truncated proteins. Such aberrant proteins can have adverse effects; for example, truncation may result in dominant-negative function. NMD therefore serves an important role in that it ensures that only intact mRNAs are translated.


RNA degradation in antiviral immunity and autoimmunity.

Rigby RE, Rehwinkel J - Trends Immunol. (2015)

Nonsense-mediated decay (NMD). NMD recognises premature translation termination codons (PTCs) and this requires translation. The mechanism of PTC definition differs between species and individual transcripts. Two major pathways are shown here. (A) One important mechanism of PTC recognition relies on a protein complex called the exon-junction complex (EJC) [9]. EJCs are deposited on mRNAs during splicing and mark exon-exon junctions. EJCs are transported together with the mRNA into the cytoplasm and are removed from the mRNA during translation [82–84]. Importantly, most mRNAs contain the stop codon in their last exon; therefore, no EJCs are left on the mRNA when translation termination occurs. However, if mRNAs have a PTC upstream of the last exon, one or multiple EJCs remain on the mRNA at the moment when translation terminates. This constellation is recognised by a number of proteins including the essential NMD effectors UPF1, UPF2, and UPF3/3X. UPF1 (red) interacts with proteins involved in translation termination, while UPF2 (orange) and UPF3/3X (yellow) associate with the EJC. If an EJC is present downstream from a terminating ribosome, the UPF proteins interact to form a complex, SMG proteins (olive) are recruited, and degradation of the mRNA is initiated (middle panel) [5–8]. (B) EJCs are not always required for NMD [5–8]. Efficient translation termination requires interactions between proteins bound to the mRNA poly(A) tail and release factors, which associate with ribosomes at stop codons. If termination occurs at a PTC, the distance to the 3′-end and poly(A) tail may be too large to accommodate this interaction (red cross) [25,85–87]. This in turn is presumed to result in delayed release of the ribosome from the mRNA, allowing for assembly of UPF proteins and recruitment of SMGs independently of an EJC.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4358841&req=5

fig0005: Nonsense-mediated decay (NMD). NMD recognises premature translation termination codons (PTCs) and this requires translation. The mechanism of PTC definition differs between species and individual transcripts. Two major pathways are shown here. (A) One important mechanism of PTC recognition relies on a protein complex called the exon-junction complex (EJC) [9]. EJCs are deposited on mRNAs during splicing and mark exon-exon junctions. EJCs are transported together with the mRNA into the cytoplasm and are removed from the mRNA during translation [82–84]. Importantly, most mRNAs contain the stop codon in their last exon; therefore, no EJCs are left on the mRNA when translation termination occurs. However, if mRNAs have a PTC upstream of the last exon, one or multiple EJCs remain on the mRNA at the moment when translation terminates. This constellation is recognised by a number of proteins including the essential NMD effectors UPF1, UPF2, and UPF3/3X. UPF1 (red) interacts with proteins involved in translation termination, while UPF2 (orange) and UPF3/3X (yellow) associate with the EJC. If an EJC is present downstream from a terminating ribosome, the UPF proteins interact to form a complex, SMG proteins (olive) are recruited, and degradation of the mRNA is initiated (middle panel) [5–8]. (B) EJCs are not always required for NMD [5–8]. Efficient translation termination requires interactions between proteins bound to the mRNA poly(A) tail and release factors, which associate with ribosomes at stop codons. If termination occurs at a PTC, the distance to the 3′-end and poly(A) tail may be too large to accommodate this interaction (red cross) [25,85–87]. This in turn is presumed to result in delayed release of the ribosome from the mRNA, allowing for assembly of UPF proteins and recruitment of SMGs independently of an EJC.
Mentions: NMD is a highly conserved mRNA surveillance pathway and has been reviewed in detail elsewhere [5–8]. Here, we will discuss only the basic principles of NMD (Figure 1). NMD detects mRNAs harbouring premature translation termination codons (PTCs) and then targets these transcripts for degradation. PTCs can arise as a consequence of gene mutations or errors during transcription. If translated, PTC-containing mRNAs encode C-terminally truncated proteins. Such aberrant proteins can have adverse effects; for example, truncation may result in dominant-negative function. NMD therefore serves an important role in that it ensures that only intact mRNAs are translated.

Bottom Line: Post-transcriptional control determines the fate of cellular RNA molecules.Recent findings have revealed a role for NMD in targeting viral RNA molecules, thereby restricting virus infection.Interestingly, NMD is also linked to immune responses at another level: mutations affecting the NMD or RNA exosome machineries cause chronic activation of defence programmes, resulting in autoimmune phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.

Show MeSH
Related in: MedlinePlus