Signaling cell death from the endoplasmic reticulum stress response

doi:10.1016/j.ceb.2010.11.003

Current Opinion in Cell Biology

Volume 23, Issue 2, April 2011, Pages 143-149

https://doi.org/10.1016/j.ceb.2010.11.003 Get rights and content

Inability to meet protein folding demands within the endoplasmic reticulum (ER) activates the unfolded protein response (UPR), a signaling pathway with both adaptive and apoptotic outputs. While some secretory cell types have a remarkable ability to increase protein folding capacity, their upper limits can be reached when pathological conditions overwhelm the fidelity and/or output of the secretory pathway. Irremediable ‘ER stress’ induces apoptosis and contributes to cell loss in several common human diseases, including type 2 diabetes and neurodegeneration. Researchers have begun to elucidate the molecular switches that determine when ER stress is too great to repair and the signals that are then sent from the UPR to execute the cell.

Introduction

The lumen of the endoplasmic reticulum (ER) is a unique cellular environment optimized to carry out the three primary tasks of this organelle: calcium storage and release, protein folding and secretion, and lipid biogenesis [1]. A range of cellular disturbances lead to accumulation of misfolded proteins in the ER, including point mutations in secreted proteins that disrupt their proper folding, sustained secretory demands on endocrine cells, viral infection with ER overload of virus-encoding protein, and loss of calcium homeostasis with detrimental effects on ER-resident calcium-dependent chaperones [2••, 3, 4]. The tripartite unfolded protein response (UPR) consists of three ER transmembrane proteins (IRE1α, PERK, ATF6) that alert the cell to the presence of misfolded proteins in the ER and attempt to restore homeostasis in this organelle by increasing ER biogenesis, decreasing the influx of new proteins into the ER, promoting the transport of damaged proteins from the ER to the cytosol for degradation, and upregulating protein folding chaperones [5]. The adaptive responses of the UPR can markedly expand the protein folding capacity of the cell and restore ER homeostasis [6]. However, if these adaptive outputs fail to compensate because ER stress is excessive or prolonged, the UPR induces cell death. The cell death pathways collectively triggered by the UPR include both caspase-dependent apoptosis and caspase-independent necrosis. While many details remain unknown, we are beginning to understand how cells determine when ER stress is beyond repair and communicate this information to the cell death machinery. For the purposes of this review, we focus on the apoptotic outputs trigged by the UPR under irremediable ER stress. While the ER contains numerous additional signaling platforms and targets that respond to diverse apoptotic stimuli (e.g. those associated with the Bap31 complex [7, 8]), their formal link to UPR-driven apoptosis remains to be determined.

Section snippets

The proximal unfolded protein response sensors

UPR signaling is initiated by three ER transmembrane proteins: IRE1α, PERK, and ATF6. The most ancient ER stress sensor, IRE1α, contains an ER lumenal domain, a cytosolic kinase domain, and a cytosolic RNase domain [9, 10]. In the presence of unfolded proteins, IRE1α’s ER lumenal domains homo-oligomerize, leading first to kinase trans-autophosphorylation and subsequent RNase activation. Dissociation of the ER chaperone BiP from IRE1α’s lumenal domain in order to engage unfolded proteins may

The BCL-2 family and the mitochondrial apoptotic pathway

A wealth of genetic and biochemical data argues that the intrinsic (mitochondrial) apoptotic pathway is the major cell death pathway induced by the UPR, at least in most cell types. This apoptotic pathway is set in motion when several toxic proteins (e.g. cytochrome c, Smac/Diablo) are released from mitochondria into the cytosol where they lead to activation of downstream effector caspases (e.g. caspase-3) [30]. The BCL-2 family, a large class of both pro- and anti-survival proteins, tightly

Initiator and executor caspases

Caspases, or cysteine-dependent aspartate-directed proteases, play essential roles in both initiating apoptotic signaling (initiator caspases-2, 4, 8, 12) and executing the final stages of cell demise (executioner caspases-3, 7, 9) [38]. The executioner caspases are proteolytically activated through either mitochondrial-dependent apoptosome formation or death receptor activation of upstream initiator caspases (i.e. caspase-8, 10). Given the prominent role of the mitochondrial apoptotic pathway

Calcium and cell death

Although an extreme depletion of ER luminal Ca²⁺ concentrations is a well-documented initiator of the UPR and ER stress-induced apoptosis or necrosis, it represents a relatively non-physiological stimulus. Given that Ca²⁺ signaling from the ER is likely coupled to most pathways leading to apoptosis, however, it is not surprising that this also extends to UPR overload. For example, recent evidence in macrophages indicates that UPR-induced activation of ERO1-α via CHOP results in stimulation of

ER stress-induced cell loss and disease

Mounting evidence suggests that ER stress-induced apoptosis contributes to a range of human diseases of cell loss, including diabetes, neurodegeneration, stroke, and heart disease, to name a few (reviewed in REF [50]). The cause of ER stress in these distinct diseases varies depending on the cell type affected and the intracellular and/or extracellular conditions that disrupt proteostasis. For example, some cases of inherited amyotrophic lateral sclerosis (ALS) are caused by toxic,

Conclusions

The UPR is a highly complex signaling pathway activated by ER stress that sends out both adaptive and apoptotic signals. All three transmembrane ER stress sensors (IRE1α, PERK, AFT6) have outputs that initially decrease the load and increase the capacity of the ER secretory pathway in an effort to restore ER homeostasis. However, under extreme ER stress, continuous engagement of IRE1α and PERK results in events that simultaneously exacerbate protein misfolding and signal death, the latter

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We thank Jason T. Williams for figure design. We apologize to those colleagues whose work we could not cite here because of space limits. Work in our laboratories is supported by grants from the Canadian Institutes of Health Research (G.S.C.); National Cancer Institute of Canada (G.S.C.); National Institutes of Health: Director's New Innovator Award DP2 OD001925 (F.R.P.), RO1 DK080955 (F.R.P.), RO1 CA136577 (S.A.O.); Sandler Program in Basic Sciences (F.R.P. and S.A.O.); Burroughs Wellcome

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View full text

Signaling cell death from the endoplasmic reticulum stress response

Introduction

Section snippets

The proximal unfolded protein response sensors

The BCL-2 family and the mitochondrial apoptotic pathway

Initiator and executor caspases

Calcium and cell death

ER stress-induced cell loss and disease

Conclusions

References and recommended reading

Acknowledgements

Nat Rev Mol Cell Biol

Nat Cell Biol

Nature

Dev Cell

Mol Cell

Mol Cell Biol

Science

Annu Rev Genet

Mol Cell Biol

Science

EMBO Rep

Mol Cancer Ther

Mol Cell

Biochim Biophys Acta

Cell

J Clin Invest

Nat Genet

Proc Natl Acad Sci U S A

Protein quality control in the early secretory pathway

EMBO J

Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes

J Clin Invest

Coxsackievirus B3 infection activates the unfolded protein response and induces apoptosis through downregulation of p58IPK and activation of CHOP and SREBP1

J Virol

ER chaperone functions during normal and stress conditions

J Chem Neuroanat

From acute ER stress to physiological roles of the unfolded protein response

Cell Death Differ

The procaspase-8 isoform, procaspase-8L, recruited to the BAP31 complex at the endoplasmic reticulum

Proc Natl Acad Sci U S A

Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol

J Cell Biol

A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells

Genes Dev

Cloning of mammalian Ire1 reveals diversity in the ER stress responses

EMBO J

BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response

PLoS Biol

On the mechanism of sensing unfolded protein in the endoplasmic reticulum

Proc Natl Acad Sci U S A