The Unfolded Protein Response: How Protein Folding Became a Restrictive Aspect for Innate Immunity and B Lymphocytes1

2011 ◽  
Vol 73 (5) ◽  
pp. 436-448 ◽  
Author(s):  
C. Z. F. Costa ◽  
S. E. A. da Rosa ◽  
M. M. de Camargo
Keyword(s):  
Innate Immunity ◽  
Protein Folding ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease

2019 ◽  
Vol 19 (21) ◽  
pp. 1902-1917 ◽  
Author(s):  
Guangyu Zhang ◽  
Xiaoding Wang ◽  
Thomas G. Gillette ◽  
Yingfeng Deng ◽  
Zhao V. Wang
Keyword(s):  
Cardiovascular Disease ◽  
Protein Folding ◽  
Unfolded Protein Response ◽  
Protein Translation ◽  
Ample Evidence ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Chronic Disturbance ◽  
The Unfolded Protein Response ◽  
Protein Response

Cardiovascular disease is the leading cause of death worldwide. Despite overwhelming socioeconomic impact and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of cardiovascular disease involve an acute or chronic disturbance in cardiac myocytes, which may lead to potent activation of the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress. Accumulation of unfolded or misfolded proteins in the Endoplasmic Reticulum (ER) elicits three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently suppresses global protein translation, augments production of protein-folding chaperones, and enhances ER-associated protein degradation, with an aim to restore cellular homeostasis. Ample evidence has established that the UPR is strongly induced in heart disease. Recently, the mechanisms of action and multiple pharmacological means to favorably modulate the UPR are emerging to curb the initiation and progression of cardiovascular disease. Here, we review the current understanding of the UPR in cardiovascular disease and discuss existing therapeutic explorations and future directions.

scholarly journals The Unfolded Protein Response as a Guardian of the Secretory Pathway

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2965
Author(s):  
Toni Radanović ◽  
Robert Ernst
Keyword(s):  
Protein Folding ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Unfolded Proteins ◽  
Storage Lipids ◽  
Unfolded Protein ◽  
Membrane Stiffness ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Membrane

The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10,000 different secretory and membrane proteins. The insertion of proteins into the membrane, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid biosynthesis including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein-folding imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.

scholarly journals The Unfolded Protein Response: A Pathway That Links Insulin Demand with β-Cell Failure and Diabetes

2008 ◽  
Vol 29 (3) ◽  
pp. 317-333 ◽  
Author(s):  
Donalyn Scheuner ◽  
Randal J. Kaufman
Keyword(s):  
Cell Death ◽  
Protein Folding ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Cell Function ◽  
Mrna Translation ◽  
Β Cell ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The endoplasmic reticulum (ER) is the entry site into the secretory pathway for newly synthesized proteins destined for the cell surface or released into the extracellular milieu. The study of protein folding and trafficking within the ER is an extremely active area of research that has provided novel insights into many disease processes. Cells have evolved mechanisms to modulate the capacity and quality of the ER protein-folding machinery to prevent the accumulation of unfolded or misfolded proteins. These signaling pathways are collectively termed the unfolded protein response (UPR). The UPR sensors signal a transcriptional response to expand the ER folding capacity, increase degredation of malfolded proteins, and limit the rate of mRNA translation to reduce the client protein load. Recent genetic and biochemical evidence in both humans and mice supports a requirement for the UPR to preserve ER homeostasis and prevent the β-cell failure that may be fundamental in the etiology of diabetes. Chronic or overwhelming ER stress stimuli associated with metabolic syndrome can disrupt protein folding in the ER, reduce insulin secretion, invoke oxidative stress, and activate cell death pathways. Therapeutic interventions to prevent polypeptide-misfolding, oxidative damage, and/or UPR-induced cell death have the potential to improve β-cell function and/or survival in the treatment of diabetes.

The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1α

2011 ◽  
Vol 91 (4) ◽  
pp. 1219-1243 ◽  
Author(s):  
Claudio Hetz ◽  
Fabio Martinon ◽  
Diego Rodriguez ◽  
Laurie H. Glimcher
Keyword(s):  
Protein Folding ◽  
Unfolded Protein Response ◽  
Signal Transduction Pathway ◽  
Secretory Cells ◽  
Factor X ◽  
Stress Sensor ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

Stress induced by accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a classic feature of secretory cells and is observed in many tissues in human diseases including cancer, diabetes, obesity, and neurodegeneration. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the nucleus and cytosol to restore ER homeostasis. Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1α), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). IRE1α signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. Here we provide an overview of the signaling and regulatory mechanisms underlying IRE1α function and discuss the emerging role of the UPR in adaptation to protein folding stress in specialized secretory cells and in pathological conditions associated with alterations in ER homeostasis.

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