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. ▪