Protein Disulfide Isomerases promote the Endoplasmic Reticulum Associated Degradation of diverse substrates using different mechanisms

Endoplasmic Reticulum Associated Degradation (ERAD) clears misfolded or incorrectly processed proteins from the ER. One family of ER resident proteins that are involved in ERAD and exhibit disulfide redox, isomerization, and chaperone activity is the Protein Disulfide Isomerase (PDI) family. In humans there are twenty PDI homologs, whereas in Saccharomyces cerevisiase there are five. To address substrate specificity among the PDI family members and their mechanisms of action during ERAD, we investigated the contributions of distinct yeast PDIs on the ERAD of model substrates that either contain disulfide bonds or lack cysteines. Through the use of a yeast expression system for Apolipoprotein B (ApoB), which is disulfide‐rich, we discovered that Pdi1 interacts with ApoB and facilitates degradation through its chaperone activity. In contrast, Pdi1's redox activity was required for the ERAD of CPY*, an ERAD substrate containing five disulfide bonds. Distinct effects of mammalian PDI homologues on ApoB degradation were then observed in hepatic cells. These data indicate that PDIs contribute to ERAD through different mechanisms.