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Getting the better of ER stress

  • RESEARCH ARTICLE
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

Research over the past few years has highlighted the ability of the unfolded protein response (UPR) to minimize the deleterious effects of accumulated misfolded proteins under both physiological and pathological conditions. The endoplasmic reticulum (ER) adapts to endogenous and exogenous stressors by expanding its protein-folding capacity and by stimulating protective processes such as autophagy and antioxidant responses. Although it is clear that severe ER stress can elicit cell death, several recent studies have shown that low levels of ER stress may actually be beneficial to cells by eliciting an adaptive UPR that ‘preconditions’ the cell to a subsequent lethal insult; this process is called ER hormesis. The findings have important implications for the treatment of a wide variety of diseases associated with defective proteostasis, including neurodegenerative diseases, diabetes, and cancer. Here, we review the physiological and pathological functions of the ER, with a particular focus on the molecular mechanisms that lead to ER hormesis and cellular protection, and discuss the implications for disease treatment.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

ALS:

Amyotrophic lateral sclerosis

ASK1:

Apoptosis signal-regulating kinase

ATF:

Activating transcription factor

CHOP:

C/EBP-homologous protein

CNS:

Central nervous system

DOG:

2-deoxy-D-glucose

DR5:

Death receptor 5

eIF2α:

Eukaryotic translation initiation factor 2α

ER:

Endoplasmic reticulum

ERAD:

ER-associated degradation

HPL-2:

Heterochromatin protein like-2

IRE1:

Inositol-requiring enzyme 1

JNK:

Jun N-terminal kinase

Keap1:

Kelch-like ECH-associated protein 1

MAM:

Mitochondrial-associated ER membranes

PERK:

Protein kinase RNA-like ER kinase

PI3K:

Phosphoinositide 3-kinase

Rh1:

Rhodopsin-1

RIDD:

Regulated IRE1-dependent decay

ROS:

Reactive oxygen species

S1P:

Site 1 protease

UPR:

Unfolded protein response

VCP:

Valosin-containing protein

XBP1:

X-box binding protein 1

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Acknowledgments

This work was supported by grants from the Fondation ARC pour la Recherche sur le Cancer (SFI20121205951) and the Centre national de la recherche scientifique to BM, and from the Ligue Nationale Contre le Cancer (Comité du rhône) and Fondation ARC pour la Recherche sur le Cancer (PJA20131200334) to SM.

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Authors and Affiliations

  1. Laboratory of Molecular Biology of the Cell, UMR5239 CNRS/Ecole Normale Supérieure de Lyon, UMS 3444 Biosciences Lyon Gerland, University of Lyon, Lyon, France

    Bertrand Mollereau & Francesco Napoletano

  2. UMR CNRS 5286, INSERM 1052, University of Lyon, Cancer Research Center of Lyon, 69000, Lyon, France

    Serge Manié

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  1. Bertrand Mollereau
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  2. Serge Manié
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  3. Francesco Napoletano
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Correspondence to Bertrand Mollereau or Francesco Napoletano.

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Mollereau, B., Manié, S. & Napoletano, F. Getting the better of ER stress. J. Cell Commun. Signal. 8, 311–321 (2014). https://doi.org/10.1007/s12079-014-0251-9

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  • DOI: https://doi.org/10.1007/s12079-014-0251-9

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