title: A novel cellular stress response characterised by a rapid reorganisation of membranes of the endoplasmic reticulum.
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.
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Varadarajan
authors.forename: E T W
authors.initials: ET
authors.lastname: Bampton
authors.forename: J L
authors.initials: JL
authors.lastname: Smalley
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: R E
authors.initials: RE
authors.lastname: Caves
authors.forename: M
authors.initials: M
authors.lastname: Butterworth
authors.forename: J
authors.initials: J
authors.lastname: Wei
authors.forename: M
authors.initials: M
authors.lastname: Pellecchia
authors.forename: J
authors.initials: J
authors.lastname: Mitcheson
authors.forename: T W
authors.initials: TW
authors.lastname: Gant
authors.forename: D
authors.initials: D
authors.lastname: Dinsdale
authors.forename: G M
authors.initials: GM
authors.lastname: Cohen
mesh_terms: D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006072:Gossypol / Q000031:analogs & derivatives / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C492806:apogossypol; D006072:Gossypol