ER stress and the unfolded protein response.

By M. Schröder, R. Kaufman. Mutation research, 2005

1,794 citations recorded by the source corpus.

Conformational diseases are caused by mutations altering the folding pathway or final conformation of a protein. Many conformational diseases are caused by mutations in secretory proteins and reach from metabolic diseases, e.g. diabetes, to developmental and neurological diseases, e.g. Alzheimer's disease. Expression of mutant proteins disrupts protein folding in the endoplasmic reticulum (ER), causes ER stress, and activates a signaling network called the unfolded protein response (UPR). The UPR increases the biosynthetic capacity of the secretory pathway through upregulation of ER chaperone and foldase expression. In addition, the UPR decreases the biosynthetic burden of the secretory pathway by downregulating expression of genes encoding secreted proteins. Here we review our current understanding of how an unfolded protein signal is generated, sensed, transmitted across the ER membrane, and how downstream events in this stress response are regulated. We propose a model in which the activity of UPR signaling pathways reflects the biosynthetic activity of the ER. We summarize data that shows that this information is integrated into control of cellular events, which were previously not considered to be under control of ER signaling pathways, e.g. execution of differentiation and starvation programs.

Subfields: Biotechnology, Cell Biology, Epidemiology

View Paper: https://www.semanticscholar.org/paper/f61b0226f572afbc58cd6c46326e24906a1e6cac

How researchers see this paper

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In Biotechnology

1. M. Boyce
2. Jianping Ye
3. Junying Yuan

In Cell Biology

1. M. Boyce
2. R. Yadav
3. Jianping Ye
4. H. Chae
5. Junying Yuan
6. Hyung-Ryong Kim
7. H. Rashid

In Epidemiology

1. M. Boyce
2. R. Yadav
3. Jianping Ye
4. H. Chae
5. M. J. Saad
6. L. Velloso
7. S. Bordin
8. Junying Yuan

Citations in the corpus

• Mechanisms of insulin resistance in obesity (2013, background): “Accumulation of unfolded or misfolded proteins is a major cause of ER stress [101].”
• Saturated Fatty Acids Produce an Inflammatory Response Predominantly through the Activation of TLR4 Signaling in Hypothalamus: Implications for the Pathogenesis of Obesity (2009, background): “Under certain harmful conditions, the ER homeostasis is disrupted, leading to the accumulation of misfolded and unfolded proteins in the ER lumen (Schröder and Kaufman, 2005; Xu et al., 2005).”
• ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells (2019, background): “UPR triggers ROS production, and ROS, in turn, can promote ER stress [65, 66].”
• Cellular response to endoplasmic reticulum stress: a matter of life or death (2006, background): “normal ER function, such as the accumulation of unfolded, misfolded or excessive protein, ER lipid or glycolipid imbalances, or changes in the redox or ionic conditions of the ER lumen.(2,3,5,6) In response to such dysfunction, the ESR acts both to increase the capacity of the ER to fold and process”
• ER stress: Autophagy induction, inhibition and selection (2015, background): “First, cells focus on translation attenuation for a few hours, thereby lessening the freshly prepared protein load into the ER until mRNAs encoding unfolded protein response (UPR) proteins are processed.(3) In a second attempt, the UPR upregulates the folding machinery by inducing ER chaperone genes”