When first inserted into the endoplasmic reticulum (ER), proteins are decorated with an elaborate, branching chain of sugars. This improves the water solubility of the proteins and helps them fold in the ER lumen. But, as proteins repeatedly try to fold into their final shape, glucose and mannose sugar rings are sequentially lopped off the original chain to yield the Man8GlcNAc2 oligosaccharide. If a protein takes too long to fold it is degraded. It was thought that Man8GlcNAc2 flagged misfolded proteins to divert them for degradation. However, this model has recently been called into question.
It turns out that the subtly different Man7GlcNAc2 sugar is the degradation flag, says author Markus Aebi; he and his team have also worked out the protein players for producing this flag and for recognizing it. Htm1p, which was known to be required for degrading misfolded proteins, trims one further mannose ring from Man8GlcNAc2 to make Man7GlcNAc2. This was unexpected because no mannosidase activity was detected when Htm1p was first characterized (although it homologous to mannosidase enzymes).
Man7GlcNAc2 is then recognized by a protein called Yos9p. This protein specifically binds to the exposed mannose residue left after Htm1p's trimming. Yos9p was already thought to “proofread” glycans that signal protein misfolding and target them for degradation, but until now the specific signal sought by Yos9p wasn't clear. The work therefore provides important insights into how this arbiter of protein quality control operates in the ER.