Role of the ubiquitin-selective CDC48UFD1/NPL4 chaperone (segregase) in ERAD of OLE1 and other substrates

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Abstract
The OLE pathway of yeast regulates the abundance of the ER‐bound enzyme Δ‐9 fatty acid desaturase OLE1, thereby controlling unsaturated fatty acid pools and membrane fluidity. Previously, we showed that this pathway is exquisitely regulated by the ubiquitin/proteasome system. Activation of the pathway involves proteasomal processing of a membrane‐bound transcription factor and the subsequent mobilization of the cleaved, ubiquitylated transcription factor from its partner molecule by CDC48UFD1/NPL4, a ubiquitin‐selective chaperone‐like enzyme. Here we report that the OLE1 protein itself is naturally short‐lived and is degraded by ubiquitin/proteasome‐dependent ER‐associated degradation (ERAD). We found that CDC48UFD1/NPL4 plays a second role in the OLE pathway by mediating ERAD of OLE1. Intriguingly, other ERAD substrates also require CDC48UFD1/NPL4 for degradation, indicating that this enzyme is a novel, constitutive component of the ERAD machinery. We propose that CDC48UFD1/NPL4 functions as a segregase that liberates ubiquitylated proteins from non‐modified partners.