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Article

High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins

View ORCID ProfileLisa Vincenz‐Donnelly, Hauke Holthusen, Roman Körner, Erik C Hansen, Jenny Presto, Jan Johansson, Ritwick Sawarkar, View ORCID ProfileF Ulrich Hartl, View ORCID ProfileMark S Hipp
DOI 10.15252/embj.201695841 | Published online 15.12.2017
The EMBO Journal (2017) e201695841
Lisa Vincenz‐Donnelly
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, GermanyMunich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Hauke Holthusen
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany
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Roman Körner
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, GermanyMunich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Erik C Hansen
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
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Jenny Presto
Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Centre for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden
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Jan Johansson
Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Centre for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden
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Ritwick Sawarkar
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
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F Ulrich Hartl
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, GermanyMunich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Mark S Hipp
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, GermanyMunich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Author Affiliations

  1. Lisa Vincenz‐Donnelly1,2,
  2. Hauke Holthusen1,
  3. Roman Körner1,2,
  4. Erik C Hansen3,
  5. Jenny Presto4,
  6. Jan Johansson4,
  7. Ritwick Sawarkar3,
  8. F Ulrich Hartl (uhartl{at}biochem.mpg.de)*,1,2 and
  9. Mark S Hipp (hipp{at}biochem.mpg.de)*,1,2
  1. 1Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany
  2. 2Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
  3. 3Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
  4. 4Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Centre for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden
  1. ↵* Corresponding author. Tel: +49 89 8578 2244; E‐mail: uhartl{at}biochem.mpg.de
    Corresponding author. Tel: +49 89 8578 2295; E‐mail: hipp{at}biochem.mpg.de
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Abstract

Protein aggregation is associated with neurodegeneration and various other pathologies. How specific cellular environments modulate the aggregation of disease proteins is not well understood. Here, we investigated how the endoplasmic reticulum (ER) quality control system handles β‐sheet proteins that were designed de novo to form amyloid‐like fibrils. While these proteins undergo toxic aggregation in the cytosol, we find that targeting them to the ER (ER‐β) strongly reduces their toxicity. ER‐β is retained within the ER in a soluble, polymeric state, despite reaching very high concentrations exceeding those of ER‐resident molecular chaperones. ER‐β is not removed by ER‐associated degradation (ERAD) but interferes with ERAD of other proteins. These findings demonstrate a remarkable capacity of the ER to prevent the formation of insoluble β‐aggregates and the secretion of potentially toxic protein species. Our results also suggest a generic mechanism by which proteins with exposed β‐sheet structure in the ER interfere with proteostasis.

Synopsis

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The quality control machinery of the ER has a remarkable capacity to maintain otherwise toxic aggregation‐prone proteins in a non‐toxic liquid‐like state, which prevents them from being secreted or retranslocated to the cytoplasm.

  • Targeting aggregation‐prone proteins to the ER strongly reduces their aggregation and toxicity.

  • The ER quality control machinery maintains aggregation‐prone proteins in a liquid‐like state.

  • Aggregation‐prone proteins are prevented from leaving the ER for secretion and are not retranslocated to the cytoplasm for degradation.

  • Aggregation‐prone proteins in the ER may interfere with the degradation of other misfolded proteins by ERAD.

  • endoplasmic reticulum
  • protein aggregation
  • proteostasis
  • quality control
  • Received October 6, 2016.
  • Revision received October 19, 2017.
  • Accepted October 25, 2017.
  • © 2017 The Authors
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Volume 37, Issue 8
13 April 2018 | pp -
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