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The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins
Misfolded proteins of the secretory pathway are extracted from the endoplasmic reticulum (ER), polyubiquitylated by a protein complex termed the Hmg-CoA reductase degradation ligase (HRD-ligase), and degraded by cytosolic 26S proteasomes. This process is termed ER-associated protein degradation (ERA...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294667/ https://www.ncbi.nlm.nih.gov/pubmed/25428985 http://dx.doi.org/10.1091/mbc.E14-07-1202 |
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author | Mehnert, Martin Sommermeyer, Franziska Berger, Maren Kumar Lakshmipathy, Sathish Gauss, Robert Aebi, Markus Jarosch, Ernst Sommer, Thomas |
author_facet | Mehnert, Martin Sommermeyer, Franziska Berger, Maren Kumar Lakshmipathy, Sathish Gauss, Robert Aebi, Markus Jarosch, Ernst Sommer, Thomas |
author_sort | Mehnert, Martin |
collection | PubMed |
description | Misfolded proteins of the secretory pathway are extracted from the endoplasmic reticulum (ER), polyubiquitylated by a protein complex termed the Hmg-CoA reductase degradation ligase (HRD-ligase), and degraded by cytosolic 26S proteasomes. This process is termed ER-associated protein degradation (ERAD). We previously showed that the membrane protein Der1, which is a subunit of the HRD-ligase, is involved in the export of aberrant polypeptides from the ER. Unexpectedly, we also uncovered a close spatial proximity of Der1 and the substrate receptor Hrd3 in the ER lumen. We report here on a mutant Hrd3KR that is selectively defective for ERAD of soluble proteins. Hrd3KR displays subtle structural changes that affect its positioning toward Der1. Furthermore, increased quantities of the ER-resident Hsp70-type chaperone Kar2 and the Hsp40-type cochaperone Scj1 bind to Hrd3KR. Of note, deletion of SCJ1 impairs ERAD of model substrates and causes the accumulation of client proteins at Hrd3. Our data imply a function of Scj1 in the removal of malfolded proteins from the receptor Hrd3, which facilitates their delivery to downstream-acting components like Der1. |
format | Online Article Text |
id | pubmed-4294667 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-42946672015-03-30 The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins Mehnert, Martin Sommermeyer, Franziska Berger, Maren Kumar Lakshmipathy, Sathish Gauss, Robert Aebi, Markus Jarosch, Ernst Sommer, Thomas Mol Biol Cell Articles Misfolded proteins of the secretory pathway are extracted from the endoplasmic reticulum (ER), polyubiquitylated by a protein complex termed the Hmg-CoA reductase degradation ligase (HRD-ligase), and degraded by cytosolic 26S proteasomes. This process is termed ER-associated protein degradation (ERAD). We previously showed that the membrane protein Der1, which is a subunit of the HRD-ligase, is involved in the export of aberrant polypeptides from the ER. Unexpectedly, we also uncovered a close spatial proximity of Der1 and the substrate receptor Hrd3 in the ER lumen. We report here on a mutant Hrd3KR that is selectively defective for ERAD of soluble proteins. Hrd3KR displays subtle structural changes that affect its positioning toward Der1. Furthermore, increased quantities of the ER-resident Hsp70-type chaperone Kar2 and the Hsp40-type cochaperone Scj1 bind to Hrd3KR. Of note, deletion of SCJ1 impairs ERAD of model substrates and causes the accumulation of client proteins at Hrd3. Our data imply a function of Scj1 in the removal of malfolded proteins from the receptor Hrd3, which facilitates their delivery to downstream-acting components like Der1. The American Society for Cell Biology 2015-01-15 /pmc/articles/PMC4294667/ /pubmed/25428985 http://dx.doi.org/10.1091/mbc.E14-07-1202 Text en © 2015 Mehnert, Sommermeyer, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Mehnert, Martin Sommermeyer, Franziska Berger, Maren Kumar Lakshmipathy, Sathish Gauss, Robert Aebi, Markus Jarosch, Ernst Sommer, Thomas The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins |
title | The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins |
title_full | The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins |
title_fullStr | The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins |
title_full_unstemmed | The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins |
title_short | The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins |
title_sort | interplay of hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294667/ https://www.ncbi.nlm.nih.gov/pubmed/25428985 http://dx.doi.org/10.1091/mbc.E14-07-1202 |
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