Proteins involved in the degradation of cytoplasmic mRNA in the major eukaryotic model systems

Abstract

The process of mRNA decay and surveillance is considered to be one of the main posttranscriptional gene expression regulation platforms in eukaryotes. The degradation of stable, protein-coding transcripts is normally initiated by removal of the poly(A) tail followed by 5'-cap hydrolysis and degradation of the remaining mRNA body by Xrn1. Alternatively, the exosome complex degrades mRNA in the 3'>5'direction. The newly discovered uridinylation-dependent pathway, which is present in many different organisms, also seems to play a role in bulk mRNA degradation. Simultaneously, to avoid the synthesis of incorrect proteins, special cellular machinery is responsible for the removal of faulty transcripts via nonsense-mediated, no-go, non-stop or non-functional 18S rRNA decay. This review is focused on the major eukaryotic cytoplasmic mRNA degradation pathways showing many similarities and pointing out main differences between the main model-species: yeast, Drosophila, plants and mammals.

Keywords: Arabidopsis thaliana; Drosophila melanogaster; Saccharomyces cerevisiae; Schizosaccharomyces pombe; human; mRNA decay; mRNA surveillance.

Figure 1.

Deadenylation-dependent degradation: pathways and enzymes. Degradation of properly synthesized mRNAs starts with shortening of the poly(A) tail (deadenylation), which is followed by decapping and subsequent 5’>3’ degradation by Xrn1 or exosome-mediated 3’>5’ degradation and cap hydrolysis. Color coding represents homologs from different organisms. Question mark indicates that relevant homolog is present in a database of a given species but its involvement in the process was not confirmed experimentally.

Figure 2.

Uridylation-dependent degradation. Properly synthesized mRNAs may be subjected to uridylation even after initial shortening of the poly(A) tail.⁶⁴ Uridylation can lead to Dis3L2-mediated 3’>5’ degradation or Lsm1-7-mediated decapping and decay. Color coding and question marks as in Figure 1.

Figure 3.

Nonsense-mediated decay. NMD in mammals often depends on the insertion of the exon-junction complex downstream of the PTC, which is not true in the case of lower eukaryotes. So far, the only model that appears to be conserved among species is the faux 3’ UTR model. a) EJC-independent NMD. In S. cerevisiae, S. pombe and D. melanogaster NMD is independent of EJC. Hrp1 downstream of a PTC (S. cerevisiae, S. pombe?), unspliced introns (S. pombe, D. melanogaster?) and extended 3’ UTRs (S. cerevisiae, S. pombe?, D. melanogaster) are the elements that can trigger NMD in these organisms. In D. melanogaster SMG1 activates UPF1 by phosphorylation. In S. cerevisiae UPF1 undergoes phosphorylation-dephosphorylation cycles,^193,194 which may indicate that, similar to higher eukaryotes, this protein is activated by a yet unknown kinase. Activation of NMD in S. cerevisiae (and probably in S. pombe) results in rapid decapping and accelerated deadenylation followed by an exonucleolytic degradation. In fruit fly cells, SMG6 endonuclease cleaves the aberrant transcripts before exonucleolytic decay. b) EJC-dependent NMD. The mammalian NMD model assumes the formation of SURF and subsequent DECID complex (ribosome:SURF:EJC). Active SMG1 phopshorylates UPF1, which causes interaction between the helicase and SMG5, SMG6 and SMG7. After the endonucleolytic cleavage by SMG6, the resulting fragments are degraded by the exosome and Xrn1.

Figure 4.

A unified model of mRNA degradation pathways triggered by ribosome stalling. a) Ribosome stalling leads to recruitment of Dom34-Hbs1 complex and yeast Ski7 protein during NGD, NSD and 18S NRD pathways. b) In the case of NGD and NSD, the recruitment of Dom34-Hbs1 induces mRNA endonucleolytic cleavage by an unknown endonuclease (mainly upstream of the stalled ribosome).¹⁸³ GTP hydrolysis results in Hbs1 dissociation and causes conformational changes in Dom34.¹⁷⁸ Rli1 binds to Dom34. c) ATP hydrolysis enables subunit dissociation.¹⁸⁶ In the case of NGD and NSD, fragments of endonucleotically cleaved mRNA are degraded by the exosome and Xrn1; nascent peptide is eliminated from the cytoplasm by the proteasome. Color coding and question marks as in Figure 1.