Two pathways must be shut down to prevent ER protein degradation.

When yeast secretory proteins are improperly folded, the ER quality control system directs them into the HRD/DER pathway, which targets the proteins for degradation. Blocking the HRD/DER pathway, however, does not completely stop degradation, implying that there must be an alternative way to destroy misfolded secretory proteins. Haynes et al., reporting on page 91, have now characterized that pathway, and suggest that it may serve to handle the overflow when the HRD/DER system gets swamped.In the HRD/DER pathway, the ubiquitin ligase Hrd1p tags defective proteins, such as a misfolded mutant form of carpoxypeptidase Y (CPY*), for degradation. The authors found that overexpressing CPY* appears to saturate the HRD/DER system, allowing direct observation of the new pathway, named Hrd1p-independent proteolysis (HIP). HIP requires ER-to-Golgi vesicular transport, and uses the ubiquitin ligase Rsp5p instead of Hrd1p.

Blocking both the HRD/DER and HIP pathways completely blocks CPY* degradation, so there do not appear to be any additional pathways for this substrate. Haynes et al. suggest that HRD/DER may be a low-capacity system that handles routine protein-folding problems, whereas HIP could act as a high-capacity system, possibly boosted by the unfolded protein response, to respond when large numbers of proteins are misfolded. ▪