Kohlmann S, et al. (2008) Ubiquitin Ligase Hul5 Is Required for Fragment-specific Substrate Degradation in Endoplasmic Reticulum-associated Degradation. J Biol Chem 283(24):16374-83
Abstract: To identify new components of the protein quality control and degradation pathway of the endoplasmic reticulum, we performed a growth-based genome wide screen of about 5000 viable deletion mutants of the yeast Saccharomyces cerevisiae. As substrates we used two misfolded ER membrane proteins: CTL* and Sec61-2L, chimeric derivatives of the classical ER degradation substrates CPY* and Sec61-2. Both substrates contain a cytosolic Leu2 protein fusion and stabilization of these substrates in ERAD deficient strains enables a restored growth of the transformed LEU2 deficient deletion mutants. We identified the strain deleted for the E4 ubiquitin ligase Hul5 among the mutant strains with a strong growth phenotype. Here we show that Hul5 is necessary for the degradation of two misfolded ER membrane substrates. While the degradation of their N-terminal parts is Hul5 independent, the breakdown of their C-terminal fragments requires the E4 activity of Hul5. In the absence of Hul5 a truncated form of CTL*myc remains to a large extent embedded in the ER membrane. Hul5 activity promotes the interaction of this truncated CTL*myc with the AAA-ATPase Cdc48, which is known to pull proteins out of the ER membrane. This study unravels the stepwise elimination of the ER membrane localized CTL*myc substrate. First, N-terminal, lumenal CPY* is transferred to the cytoplasm and degraded by the proteasome. Subsequently, the remaining C-terminal membrane anchored part requires Hul5 for its effective extraction out of the endoplasmic reticulum and proteasomal degradation.
|Status: Published||Type: Journal Article||PubMed ID: 18436532|
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