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Related Concept Videos

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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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The Unfolded Protein Response01:37

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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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Role of ER in the Secretory Pathway01:17

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Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
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GPI-anchoring is a post-translational, reversible protein modification that is ubiquitous in eukaryotes. Such proteins are primarily present on the exoplasmic leaflet of the plasma membrane.
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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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Related Experiment Video

Updated: Jun 27, 2025

Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules
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Mammalian IRE1α dynamically and functionally coalesces with stress granules.

Songzi Liu1, Xiaoge Zhang1, Xin Yao1

  • 1Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences; TaiKang Center for Life and Medical Sciences; the Institute for Advanced Studies; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.

Nature Cell Biology
|May 7, 2024
PubMed
Summary

Endoplasmic reticulum (ER) stress triggers inositol-requiring enzyme 1 (IRE1) clustering with stress granules (SGs) via phase separation. This IRE1-SG condensate formation enhances the pro-survival X-box-binding protein 1 (XBP1) pathway during cellular stress.

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR).
  • Inositol-requiring enzyme 1 (IRE1) is a key sensor and effector in the UPR pathway.
  • Activated IRE1 forms clusters, but their structure and function are poorly understood.

Purpose of the Study:

  • To investigate the dynamic architecture and functional properties of IRE1 clusters during ER stress.
  • To elucidate the mechanism underlying IRE1 cluster formation and its relationship with stress granules (SGs).
  • To understand how IRE1 clustering impacts the efficiency of the IRE1-XBP1 pathway.

Main Methods:

  • Utilized mammalian cell models to study IRE1α clustering dynamics.
  • Investigated the role of intrinsically disordered regions in IRE1α's cytosolic linker.
  • Assessed the impact of disrupting SG assembly on IRE1α clustering and XBP1 splicing.

Main Results:

  • IRE1α cluster formation is an ER membrane-bound phase separation event coupled to SG assembly.
  • IRE1α clusters are dynamically tethered to SGs at the ER in response to various stressors.
  • Disruption of SG assembly abrogated IRE1α clustering and impaired XBP1 mRNA splicing.
  • IRE1α-SG coalescence enriched pro-survival pathway components, enhancing stress handling capacity.

Conclusions:

  • IRE1α clustering represents a phase transition mechanism involving SG coalescence.
  • This spatiotemporal assembly of IRE1α-SG condensates optimizes IRE1α machinery function.
  • The findings reveal a novel mechanism for enhanced cellular stress resilience via the IRE1-XBP1 pathway.