Abstract
Canonical endoplasmic reticulum (ER) stress, which occurs in many physiological and disease processes, results in activation of the unfolded protein response (UPR). We now describe a new, evolutionarily conserved cellular stress response characterised by a striking, but reversible, reorganisation of ER membranes that occurs independently of the UPR, resulting in impaired ER transport and function. This reorganisation is characterised by a dramatic redistribution and clustering of ER membrane proteins. ER membrane aggregation is regulated, in part, by anti-apoptotic BCL-2 family members, particularly MCL-1. Using connectivity mapping, we report the widespread occurrence of this stress response by identifying several structurally diverse chemicals from different pharmacological classes, including antihistamines, antimalarials and antipsychotics, which induce ER membrane reorganisation. Furthermore, we demonstrate the potential of ER membrane aggregation to result in pathological consequences, such as the long-QT syndrome, a cardiac arrhythmic abnormality, arising because of a novel trafficking defect of the human ether-a-go-go-related channel protein from the ER to the plasma membrane. Thus, ER membrane reorganisation is a feature of a new cellular stress pathway, clearly distinct from the UPR, with important consequences affecting the normal functioning of the ER.
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Abbreviations
- CHOP:
-
C/EBP homologous protein
- CLL:
-
chronic lymphocytic leukaemia
- ER:
-
endoplasmic reticulum
- hERG:
-
human ether-a-go-go-related gene
- IRE1α:
-
inositol-requiring protein-1α
- LQTS:
-
long-QT syndrome
- MCL-1:
-
myeloid cell leukaemia 1
- NDGA:
-
nordihydroguaiaretic acid
- PERK:
-
protein kinase RNA-like ER kinase
- THG:
-
thapsigargin
- UPR:
-
unfolded protein response
- VSVG:
-
vesicular stomatitis viral glycoprotein
- XBP1:
-
X-box-binding protein 1
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Acknowledgements
We thank Drs Bratton, Downward, Glimcher, Harding, Mollard, Rosenberg and Shore for cells and reagents, and Professor A Willis for helpful discussions. We thank Judy McWilliam, Tim Smith and Kate Phillips for technical assistance, and the Medical Research Council for core support. We thank the NIH (grant CA149668 to MP) for support.
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Varadarajan, S., Bampton, E., Smalley, J. et al. A novel cellular stress response characterised by a rapid reorganisation of membranes of the endoplasmic reticulum. Cell Death Differ 19, 1896–1907 (2012). https://doi.org/10.1038/cdd.2012.108
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DOI: https://doi.org/10.1038/cdd.2012.108
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