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

Author:

Lay Angelina J.123,Dupuy Alexander14,Hagimola Lejla13,Tieng Jessica123,Larance Mark5ORCID,Zhang Yunwei6ORCID,Yang Jean6ORCID,Kong Yvonne14,Chiu Joyce23ORCID,Gray Emilia13,Qin Zihao14ORCID,Schmidt Diana13,Maclean Jessica37ORCID,Hofma Benjamin37ORCID,Ellis Marc37ORCID,Kalev-Zylinska Maggie8ORCID,Argon Yair9ORCID,Jackson Shaun P.37ORCID,Hogg Philip23ORCID,Passam Freda H.14ORCID

Affiliation:

1. 1Haematology Research Group, Heart Research Institute, Sydney, Australia

2. 2The Centenary Institute, Sydney, Australia

3. 3University of Sydney, Sydney, Australia

4. 4Faculty Medicine Health, Central Clinical School, University of Sydney, Sydney, Australia

5. 5Faculty Medicine Health, School of Medical Sciences, University of Sydney, Sydney, Australia

6. 6Sydney Precision Bioinformatics Alliance, School of Mathematics and Statistics, University of Sydney, Sydney, Australia

7. 7Thrombosis Research Group, Heart Research Institute, Sydney, Australia

8. 8Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand

9. 9Division of Cell Pathology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Hematology

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