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Endoplasmic reticulum protein 5 attenuates platelet endoplasmic reticulum stress and secretion in a mouse model
Journal article   Open access   Peer reviewed

Endoplasmic reticulum protein 5 attenuates platelet endoplasmic reticulum stress and secretion in a mouse model

Angelina J Lay, Alexander Dupuy, Lejla Hagimola, Jessica Tieng, Mark Larance, Yunwei Zhang, Jean Yang, Yvonne Kong, Joyce Chiu, Emilia Gray, …
Blood advances, Vol.7(9), pp.1650-1665
2023
PMID: 36508284
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Published3.68 MBDownloadView
CC BY-NC-ND V4.0 Open Access

Abstract

Animals Blood Platelets - metabolism Hemostasis Mice Platelet Aggregation Protein Disulfide-Isomerases - genetics Protein Disulfide-Isomerases - metabolism Thrombosis - metabolism
Extracellular protein disulfide isomerases (PDIs), including PDI, endoplasmic reticulum protein 57 (ERp57), ERp72, ERp46, and ERp5, are required for in vivo thrombus formation in mice. Platelets secrete PDIs upon activation, which regulate platelet aggregation. However, platelets secrete only ∼10% of their PDI content extracellularly. The intracellular role of PDIs in platelet function is unknown. Here, we aim to characterize the role of ERp5 (gene Pdia6) using platelet conditional knockout mice, platelet factor 4 (Pf4) Cre+/ERp5floxed (fl)/fl. Pf4Cre+/ERp5fl/fl mice developed mild macrothrombocytopenia. Platelets deficient in ERp5 showed marked dysregulation of their ER, indicated by a twofold upregulation of ER proteins, including PDI, ERp57, ERp72, ERp46, 78 kilodalton glucose-regulated protein (GRP78), and calreticulin. ERp5-deficient platelets showed an enhanced ER stress response to ex vivo and in vivo ER stress inducers, with enhanced phosphorylation of eukaryotic translation initiation factor 2A and inositol-requiring enzyme 1 (IRE1). ERp5 deficiency was associated with increased secretion of PDIs, an enhanced response to thromboxane A2 receptor activation, and increased thrombus formation in vivo. Our results support that ERp5 acts as a negative regulator of ER stress responses in platelets and highlight the importance of a disulfide isomerase in platelet ER homeostasis. The results also indicate a previously unanticipated role of platelet ER stress in platelet secretion and thrombosis. This may have important implications for the therapeutic applications of ER stress inhibitors in thrombosis.

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Collaboration types
Domestic collaboration
International collaboration
Citation topics
1 Clinical & Life Sciences
1.127 Molecular & Cell Biology - Pharmacology
1.127.973 Thiol-Disulfide Systems
Web Of Science research areas
Hematology
ESI research areas
Clinical Medicine
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