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Structure and Function of Platelets01:18

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The cell fragments known as platelets are disc-shaped, with an average diameter of about 3 μm and a thickness of roughly 1 μm. They play a crucial role in the body's vascular clotting system, which also involves plasma proteins, blood cells, and blood vessel tissues.
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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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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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Related Experiment Video

Updated: Sep 4, 2025

Comprehensive Analysis of Procoagulant Platelets Exhibiting Features of Necrosis, Apoptosis and Platelet Activation
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Unfolded Protein Response Differentially Modulates the Platelet Phenotype.

Kanika Jain1, Tarun Tyagi1, Jing Du1

  • 1Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.

Circulation Research
|July 21, 2022
PubMed
Summary

Platelets activate the unfolded protein response (UPR) independently of genomic regulation. Targeting UPR pathways offers a novel antiplatelet strategy for cardiovascular diseases like diabetes.

Keywords:
blood plateletsdiabetes mellitusendoplasmic reticulum stressplatelet activationprotein aggregatesunfolded protein response

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Area of Science:

  • Cardiovascular Biology
  • Cellular Stress Response
  • Platelet Physiology

Background:

  • The unfolded protein response (UPR) is crucial for alleviating protein misfolding in nucleated cells.
  • UPR's role in anucleate platelets, despite their association with cardiovascular diseases, remains undescribed.
  • Platelets rapidly respond to blood stressors, suggesting a potential role for UPR.

Purpose of the Study:

  • To investigate the presence and function of UPR in anucleate platelets.
  • To explore the specific UPR pathways activated by different stressors in platelets.
  • To determine the impact of UPR modulation on platelet physiology and function.

Main Methods:

  • Ex vivo and in vivo studies using human and mouse platelets.
  • Generation of platelet lineage-specific knockout mice for PERK, XBP1, and ATF6 pathways.
  • Evaluation of platelets from diabetes patients for UPR activation under chronic disease conditions.

Main Results:

  • Tunicamycin induced IRE1α-XBP1; oxidative stress activated PERK in platelets.
  • PERK or XBP1 deficiency increased platelet aggregation and altered signaling pathways.
  • ATF6 deletion had a modest effect, while diabetes patient platelets showed IRE1α-XBP1 activation correlated with disease severity.
  • IRE1α inhibition increased aggregation; sodium 4-phenylbutyrate reduced hyperactivation.

Conclusions:

  • UPR is activated in platelets, independent of genomic regulation, with stress-specific pathway induction.
  • Each UPR pathway differentially modulates platelet activation and phenotype.
  • Targeting specific UPR arms presents a novel antiplatelet strategy for thrombotic risk in cardiovascular diseases.