Role of the ubiquitin-selective CDC48^UFD1/NPL4 chaperone (segregase) in ERAD of OLE1 and other substrates.

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 (EI4AD). We found that CDC48UFD1/NPL4 plays a second role in the OLE pathway by mediating ERAD of OLE 1. Intriguingly, other ERAD substrates also require CDC48UFD1/NPL4 for degradation, indicating that this enzyme is a novel, constitutive component of the EI4AD machinery. We propose that CDC48UFD1/NPL4 functions as a segregase that liberates ubiquitylated proteins from non-modified partners. [ABSTRACT FROM AUTHOR]