Molecular Characteristics
Overview: SMG8 encodes a component of the SURF (SMG1, UPF1, and the eukaryotic release factors 1 and 3) complex, which plays an important role in nonsense-mediated mRNA decay (NMD). This process protects the cell from the negative effects of truncated proteins through detecting and degrading transcripts containing premature stop codons (PTC).
Mechanism: NMD is a complex process that has been preserved in all eukaryotes studied to date. The current model suggests that a UPF2-UPF3B complex flags exon-exon junction and will initiate a process that leads to the destruction of PTC-containing transcripts if encountered downstream of a stop codon. The most important step in this process involves the phosphorylation of UPF1 by SMG1, which requires the action of two proteins, SMG8 and SMG9, in the SURF complex. The SURF complex assembles on ribosomes that encounter a PTC. When phosphorylated, UPF1 recruits SMG5, SMG6, and SMG7, releases eRF1 and eRF3, and stops the translation of the mRNA. The PTC-containing mRNA is degraded through SMG5–SMG7-mediated exonucleolytic decay and SMG6-mediated endonucleolytic decay.
Mutations and pathophysiology
SMG8 is located at 17q22. The first study to link this gene to human disease identified four different, homozygous, loss-of-function mutations (GenBank: NM_018149.6) in four different families:
c.441dupA (p.Val148-SerfsTer11) in family 1
c.2515C>T (p.Arg839Ter) in family 2
c.623A>G (p.His208Arg) in family 3
c.1125dup (p.Pro376Alafs*2) in family 4
These variants were predicted to lead a decrease in SMG8 activity. Genetic analysis revealed that SMG8-depleted cells display increased the phosphorylation of UPF1. Consequently, NMD activity in these cells was reduced.