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Related Concept Videos

The Unfolded Protein Response01:37

The Unfolded Protein Response

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Regulation of the Unfolded Protein Response01:31

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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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Protein Modifications in the RER01:26

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Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
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Redox Reactions01:27

Redox Reactions

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Redox reactions are vital biochemical processes that underpin energy metabolism in cells. These reactions involve the transfer of electrons between molecules, occurring in tandem as oxidation and reduction. Oxidation refers to the loss of electrons, while reduction denotes their gain. This coupling ensures the seamless flow of electrons through metabolic pathways. For example, in bacterial metabolism, glucose undergoes oxidation to carbon dioxide, while oxygen is simultaneously reduced to...
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Redox Reactions01:24

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Oxidation-reduction or redox reactions involve the transfer of electrons from one molecule or atom to another. When an atom gains an electron, another atom must lose an electron, meaning oxidation and reduction must occur together. Since the redox occurs in pairs, the atom that gets oxidized is also called the reducing agent or reductant, and the atom that is reduced is also called the oxidizing agent or oxidant. A straightforward way to remember the definitions of oxidation and reduction is...
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Protein Folding Quality Check in the RER01:29

Protein Folding Quality Check in the RER

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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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Related Experiment Video

Updated: Apr 26, 2026

Defining Hsp33's Redox-regulated Chaperone Activity and Mapping Conformational Changes on Hsp33 Using Hydrogen-deuterium Exchange Mass Spectrometry
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Redox controls UPR to control redox.

Davide Eletto1, Eric Chevet2, Yair Argon3

  • 1Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA 19104, USA davide.laptop@gmail.com christian.appenzeller@unibas.ch.

Journal of Cell Science
|August 10, 2014
PubMed
Summary
This summary is machine-generated.

Cellular redox conditions and the unfolded protein response (UPR) dictate cell fate. Redox cues activate UPR, influencing cell adaptation or death through ER-mitochondrial crosstalk and amplification loops.

Keywords:
Endoplasmic reticulumEndoplasmic reticulum stressMitochondriaProtein disulfide isomeraseReactive oxygen speciesUnfolded protein response

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Assessment of Cellular Oxidation using a Subcellular Compartment-Specific Redox-Sensitive Green Fluorescent Protein
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Area of Science:

  • Cellular Biology
  • Biochemistry
  • Physiology

Background:

  • Intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are crucial for cell life and death decisions.
  • UPR is initiated by endoplasmic reticulum (ER) stress, a disruption of ER homeostasis, leading to either cell adaptation or demise based on stress severity and duration.

Purpose of the Study:

  • To review the mechanisms by which redox conditions activate the UPR.
  • To discuss the remodeling of cellular oxidant and antioxidant capacities downstream of UPR signals.
  • To explore the role of ER-mitochondrial crosstalk in UPR.
  • To propose that redox-based amplification loops contribute to the switch from adaptive to fatal UPR.

Main Methods:

  • Review of existing literature on UPR activation and redox signaling.
  • Analysis of direct interactions between protein disulfide isomerases and ER stress sensors.
  • Examination of protein S-nitrosylation and ER Ca(2+) efflux.
  • Discussion of NADPH oxidase activation, mitogen-activated protein kinases, and transcriptional antioxidant responses.
  • Exploration of ER-mitochondrial crosstalk.

Main Results:

  • Redox conditions can directly activate UPR through mechanisms including protein disulfide isomerases, S-nitrosylation, and reactive oxygen species-promoted ER Ca(2+) efflux.
  • Downstream of UPR signals, cellular redox balance is remodeled via NADPH oxidases, MAPKs, transcriptional responses, and ER-mitochondrial crosstalk.
  • Redox cues act as both triggers and effectors of ER stress, creating amplification loops.

Conclusions:

  • Redox-based amplification loops are critical in mediating the transition from adaptive to fatal UPR.
  • Understanding these redox-driven UPR mechanisms is key to deciphering cell fate decisions under stress.