ArticleBlood2022
A novel role for endoplasmic reticulum protein 46 (ERp46) in platelet function and arterial thrombosis in mice.
Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- High-resolution cryo-EM structure of integrin αIIbβ3 bound to disease-causing maternal HPA-1a antibody that blocks integrin activation.Science advances · 2026Article
- Allosteric Disulfide Bridges in Integrins: The Molecular Switches of Redox Regulation of Integrin-Mediated Cell Functions.Antioxidants (Basel, Switzerland) · 2025Review
- Extracellular PDI in thrombosis and vascular injury.Thrombosis journal · 2025Review
- Galloylated polyphenols represent a new class of antithrombotic agents with broad activity against thiol isomerases.Journal of thrombosis and haemostasis : JTH · 2025Article
- Endoplasmic reticulum protein 29 negatively regulates platelet functions and thrombosis in mice.Thrombosis journal · 2025Article
- Transmembrane thiol isomerase TMX1 inhibits fibrin formation by down-regulation of platelet phosphatidylserine exposure.Cell communication and signaling : CCS · 2025Article
- Development of Zafirlukast Analogues for Improved Antithrombotic Activity Through Thiol Isomerase Inhibition.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Redox regulation: mechanisms, biology and therapeutic targets in diseases.Signal transduction and targeted therapy · 2025Review
- Recent advances in vascular thiol isomerases: insights into structures, functions in thrombosis and antithrombotic inhibitor development.Thrombosis journal · 2025Review
- Thiol isomerase ERp18 enhances platelet activation and arterial thrombosis.Research and practice in thrombosis and haemostasis · 2025Article
- Platelets welcome a new protein disulfide isomerase family member.Journal of thrombosis and haemostasis : JTH · 2025Article
- A novel role for protein disulfide isomerase ERp18 in venous thrombosis.Thrombosis journal · 2024Article
- Transmembrane thiol isomerase TMX1 counterbalances the effect of ERp46 to inhibit platelet activation and integrin αIIbβ3 function.Research and practice in thrombosis and haemostasis · 2024Article
- Recent advances in vascular thiol isomerases and redox systems in platelet function and thrombosis.Journal of thrombosis and haemostasis : JTH · 2024Review
- Thioredoxin-related transmembrane protein 1 negatively regulates coagulation and phosphatidylserine exposure.Research and practice in thrombosis and haemostasis · 2024Article
- Thioredoxin Domain Containing 5 (TXNDC5): Friend or Foe?Current issues in molecular biology · 2024Review
- Disturbed flow regulates protein disulfide isomerase A1 expression via microRNA-204.Frontiers in physiology · 2024Article
- Endoplasmic reticulum protein 5 attenuates platelet endoplasmic reticulum stress and secretion in a mouse model.Blood advances · 2023Article
- Structure, signal transduction, activation, and inhibition of integrin αIIbβ3.Thrombosis journal · 2023Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
Although several members of protein disulfide isomerase (PDI) family support thrombosis, other PDI family members with the CXYC motif remain uninvestigated. ERp46 has 3 CGHC redox-active sites and a radically different molecular architecture than other PDIs. Expression of ERp46 on the platelet surface increased with thrombin stimulation. An anti-ERp46 antibody inhibited platelet aggregation, adenosine triphosphate (ATP) release, and αIIbβ3 activation. ERp46 protein potentiated αIIbβ3 activation, platelet aggregation, and ATP release, whereas inactive ERp46 inhibited these processes. ERp46 knockout mice had prolonged tail-bleeding times and decreased platelet accumulation in thrombosis models that was rescued by infusion of ERp46. ERp46-deficient platelets had decreased αIIbβ3 activation, platelet aggregation, ATP release, and P-selectin expression. The defects were reversed by wild-type ERp46 and partially reversed by ERp46 containing any of the 3 active sites. Platelet aggregation stimulated by an αIIbβ3-activating peptide was inhibited by the anti-ERp46 antibody and was decreased in ERp46-deficient platelets. ERp46 bound tightly to αIIbβ3 by surface plasmon resonance but poorly to platelets lacking αIIbβ3 and physically associated with αIIbβ3 upon platelet activation. ERp46 mediated clot retraction and platelet spreading. ERp46 more strongly reduced disulfide bonds in the β3 subunit than other PDIs and in contrast to PDI, generated thiols in β3 independently of fibrinogen. ERp46 cleaved the Cys473-Cys503 disulfide bond in β3, implicating a target for ERp46. Finally, ERp46-deficient platelets have decreased thiols in β3, implying that ERp46 cleaves disulfide bonds in platelets. In conclusion, ERp46 is critical for platelet function and thrombosis and facilitates αIIbβ3 activation by targeting disulfide bonds.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.