NDLI: Ubiquitin ligase Hul5 is required for fragment-specific substrate degradation in endoplasmic reticulum-associated degradation.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Wolf, Dieter H. Kohlmann, Sonja Schäfer, Antje
Description	Author Affiliation: Kohlmann S ( Institut für Biochemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany.)
Abstract	To identify new components of the protein quality control and degradation pathway of the endoplasmic reticulum (ER), 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 ER-associated degradation-deficient strains enables a restored growth of the transformed LEU2-deficient deletion mutants. We identified the strain deleted for the ubiquitin chain elongating 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. Although the degradation of their N-terminal parts is Hul5-independent, the breakdown of their C-terminal fragments requires the ubiquitin chain elongating ligase activity of Hul5. In the absence of Hul5, a truncated form of CTLmyc remains to a large extent embedded in the ER membrane. Hul5 activity promotes the interaction of this truncated CTLmyc 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 CTLmyc 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.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	24
Volume Number	283
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2008-06-13
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Endoplasmic Reticulum Metabolism Proteasome Endopeptidase Complex Saccharomyces Cerevisiae Proteins Saccharomyces Cerevisiae Ubiquitin-Protein Ligases Adenosine Triphosphatases Chemistry Cell Cycle Proteins Cycloheximide Pharmacology Cytoplasm Fungal Proteins Gene Expression Regulation, Fungal Models, Biological Mutation Protein Folding Protein Structure, Tertiary Subcellular Fractions Time Factors Research Support, Non-U.S. Gov't Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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