Top

Research Article

Split Viewer

Mol. Cells 2013; 35(4): 291-297

Published online April 30, 2013

https://doi.org/10.1007/s10059-013-2286-9

© The Korean Society for Molecular and Cellular Biology

Inhibition of Endoplasmic Reticulum Associated Degradation Reduces Endoplasmic Reticulum Stress and Alters Lysosomal Morphology and Distribution

Hyung Lim Elfrink, Rob Zwart, Frank Baas, and Wiep Scheper

1Department of Genome Analysis, 2Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands

Received: November 1, 2013; Revised: February 6, 2013; Accepted: February 13, 2013

Abstract

Disturbances in proteostasis are observed in many neurodegenerative diseases. This leads to activation of protein
quality control to restore proteostasis, with a key role for the removal of aberrant proteins by proteolysis. The
unfolded protein response (UPR) is a protein quality control mechanism of the endoplasmic reticulum (ER) that is
activated in several neurodegenerative diseases. Recently we showed that the major proteolytic pathway during UPR
activation is via the autophagy/lysosomal system. Here we investigate UPR induction if the other major proteolytic
pathway of the ER -ER associated degradation (ERAD)- is inhibited. Surprisingly, impairment of ERAD results in decreased
UPR activation and protects against ER stress toxicity. Autophagy induction is not affected under these
conditions, however, a striking relocalization of the lysosomes is observed. Our data suggest that a protective
UPR-modulating mechanism is activated if ERAD is inhibited, which involves lysosomes. Our data provide insight
in the cross-talk between proteolytic pathways involved in ER proteostasis. This has implications for neurodegenerative
diseases like Alzheimer’s disease where disturbed ER proteostasis and proteolytic impairment are early phenomena
in the pathology.

Keywords Alzheimer's disease, endoplasmic reticulum stress, lysosome, unfolded protein response

Article

Research Article

Mol. Cells 2013; 35(4): 291-297

Published online April 30, 2013 https://doi.org/10.1007/s10059-013-2286-9

Copyright © The Korean Society for Molecular and Cellular Biology.

Inhibition of Endoplasmic Reticulum Associated Degradation Reduces Endoplasmic Reticulum Stress and Alters Lysosomal Morphology and Distribution

Hyung Lim Elfrink, Rob Zwart, Frank Baas, and Wiep Scheper

1Department of Genome Analysis, 2Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands

Received: November 1, 2013; Revised: February 6, 2013; Accepted: February 13, 2013

Abstract

Disturbances in proteostasis are observed in many neurodegenerative diseases. This leads to activation of protein
quality control to restore proteostasis, with a key role for the removal of aberrant proteins by proteolysis. The
unfolded protein response (UPR) is a protein quality control mechanism of the endoplasmic reticulum (ER) that is
activated in several neurodegenerative diseases. Recently we showed that the major proteolytic pathway during UPR
activation is via the autophagy/lysosomal system. Here we investigate UPR induction if the other major proteolytic
pathway of the ER -ER associated degradation (ERAD)- is inhibited. Surprisingly, impairment of ERAD results in decreased
UPR activation and protects against ER stress toxicity. Autophagy induction is not affected under these
conditions, however, a striking relocalization of the lysosomes is observed. Our data suggest that a protective
UPR-modulating mechanism is activated if ERAD is inhibited, which involves lysosomes. Our data provide insight
in the cross-talk between proteolytic pathways involved in ER proteostasis. This has implications for neurodegenerative
diseases like Alzheimer’s disease where disturbed ER proteostasis and proteolytic impairment are early phenomena
in the pathology.

Keywords: Alzheimer's disease, endoplasmic reticulum stress, lysosome, unfolded protein response

Mol. Cells
May 31, 2022 Vol.45 No.5, pp. 273~352
COVER PICTURE
Fe2+ ion depletion-induced expression of BΔGFP at the early stage of leaf development (Choi et al., pp. 294-305).

Supplementary File

Share this article on

  • line
  • mail

Molecules and Cells

eISSN 0219-1032
qr-code Download