Journal Article

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

Kim, Inki, Xu, Wenjie, Reed, John C.

2008

Overview

Key Points 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. Endoplasmic reticulum (ER) stress is induced following the accumulation of unfolded proteins in the ER. This triggers the unfolded protein response, which initially acts to compensate for damage, but if prolonged or excessive can trigger cell death. Here, Reed and colleagues discuss the role of ER-initiated cell death pathways in diseases including neurodegeneration, hypoxia, heart disease, diabetes and immune disorders, while identifying promising therapeutic targets. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathological conditions. These include hypoxia, oxidative injury, high-fat diet, hypoglycaemia, protein inclusion bodies and viral infection. ER stress triggers an evolutionarily conserved series of signal-transduction events, which constitutes the unfolded protein response. These signalling events aim to ameliorate the accumulation of unfolded proteins in the ER; however, when these events are severe or protracted they can induce cell death. With the increasing recognition of an association between ER stress and human diseases, and with the improved understanding of the diverse underlying molecular mechanisms, novel targets for drug discovery and new strategies for therapeutic intervention are beginning to emerge.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Antineoplastic Agents - chemical synthesis / Antineoplastic Agents - therapeutic use / Apoptosis - physiology / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cancer Research / Cell death / Cell Death - physiology / Drug Design / eIF-2 Kinase - metabolism / Endoplasmic reticulum / Endoplasmic Reticulum - physiology / Health aspects / Heat shock proteins / Humans / Medicinal Chemistry / Molecular Chaperones - physiology / Molecular Medicine / Neoplasms - drug therapy / Neoplasms - physiopathology / Neurodegenerative Diseases - physiopathology / Oxidative Stress / Pharmacology/Toxicology / Physiological aspects / Prevention / Protein Denaturation / Protein Folding / Reperfusion Injury - physiopathology / review-article / Risk factors / Signal Transduction / Stress, Physiological