Identification of SEC61B as a novel regulator of calcium flux and platelet hyperreactivity in diabetes mellitus
Abstract High platelet reactivity is associated with adverse clinical events and is more frequent in people with diabetes mellitus (DM). To better understand platelet dysfunction in DM, we performed a proteomic analysis in platelets from a matched cohort of 34 people without, and 42 people with type 2 DM. The cohorts were matched by clinical characteristics including age, sex, and coronary artery disease burden. Using high sensitivity unbiased proteomics, we consistently identified over 2,400 intracellular proteins, and detected proteins that are differentially released by platelets from people with diabetes in response to low dose thrombin. Importantly, we identified the endoplasmic reticulum (ER) protein SEC61 translocon subunit beta (SEC61B) was increased in platelets from humans and mice within vivohyperglycemia. SEC61B was increased in megakaryocytes in mouse models of diabetes, in association with megakaryocyte ER stress. A rise in cytosolic calcium is a key aspect in platelet activation, and the SEC61 translocon is known to act as a channel for ER calcium leak. We demonstrate that cultured cells overexpressing SEC61B have increased calcium flux and decreased protein synthesis. In accordance, hyperglycemic mouse platelets mobilized more calcium to the cytosol and had lower protein synthesis compared with normoglycemic platelets. Independently,in vitroinduction of ER stress increased platelet SEC61B expression and markers of platelet activation. We propose a mechanism whereby ER stress-induced upregulation of platelet SEC61B leads to increased cytosolic calcium, potentially contributing to platelet hyperactivity in people with diabetes.Key Points <jats:list list-type="order">Platelet SEC61B is increased in hyperglycemia and contributes to increased endoplasmic reticulum (ER) calcium leakIncreased ER calcium leak is associated with ER stress and platelet hyperactivity.
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 27. Feb. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kong, Yvonne X [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.02.20.581175 |
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| PPN (Katalog-ID): |
XBI042650348 |
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| 245 | 1 | 0 | |a Identification of SEC61B as a novel regulator of calcium flux and platelet hyperreactivity in diabetes mellitus |
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| 520 | |a Abstract High platelet reactivity is associated with adverse clinical events and is more frequent in people with diabetes mellitus (DM). To better understand platelet dysfunction in DM, we performed a proteomic analysis in platelets from a matched cohort of 34 people without, and 42 people with type 2 DM. The cohorts were matched by clinical characteristics including age, sex, and coronary artery disease burden. Using high sensitivity unbiased proteomics, we consistently identified over 2,400 intracellular proteins, and detected proteins that are differentially released by platelets from people with diabetes in response to low dose thrombin. Importantly, we identified the endoplasmic reticulum (ER) protein SEC61 translocon subunit beta (SEC61B) was increased in platelets from humans and mice within vivohyperglycemia. SEC61B was increased in megakaryocytes in mouse models of diabetes, in association with megakaryocyte ER stress. A rise in cytosolic calcium is a key aspect in platelet activation, and the SEC61 translocon is known to act as a channel for ER calcium leak. We demonstrate that cultured cells overexpressing SEC61B have increased calcium flux and decreased protein synthesis. In accordance, hyperglycemic mouse platelets mobilized more calcium to the cytosol and had lower protein synthesis compared with normoglycemic platelets. Independently,in vitroinduction of ER stress increased platelet SEC61B expression and markers of platelet activation. We propose a mechanism whereby ER stress-induced upregulation of platelet SEC61B leads to increased cytosolic calcium, potentially contributing to platelet hyperactivity in people with diabetes.Key Points <jats:list list-type="order">Platelet SEC61B is increased in hyperglycemia and contributes to increased endoplasmic reticulum (ER) calcium leakIncreased ER calcium leak is associated with ER stress and platelet hyperactivity | ||
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