Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities

Perturbations of the endoplasmic reticulum (ER) caused by accumulation of unfolded proteins in this organelle trigger signal-transduction responses that assist with restoration of homeostasis during short-term but contribute to pathology when prolonged, including causing cell death.Among the stimuli that trigger ER stress are hypoxia, oxidative injury, a high-fat diet, hypoglycaemia, protein-inclusion bodies and viral infection, thus linking these organelle-initiated responses to a diversity of diseases, including cancer, autoimmunity, diabetes, heart disease, stroke and neurodegeneration.With increasing recognition of ER stress in association with human diseases and with improving understanding of the underlying molecular mechanisms, novel targets for drug discovery and new strategies for therapeutic intervention are beginning to emerge from the study of ER stress.Scenarios in which ER stress contributes to disease are outlined and prospects for drug discovery are discussed.Among the cell death mechanisms addressed are: pro-apoptotic signals resulting from activation of the ER-associated kinase IRE1, an upstream activator of apoptotic signalling kinase 1 (ASK1) that activates a stress kinase pathway affecting the activity or expression of several apoptosis regulators including BCL-2, BIM and CHOP; cytoprotective ER-membrane-associated proteins that modulate ER stress signalling; and the interplay among ER-initiated signal-transduction mechanisms that control apoptosis, necrosis and autophagy.