Elsevier

Redox Biology

Volume 50, April 2022, 102244
Redox Biology

The extracellular Ero1α/PDI electron transport system regulates platelet function by increasing glutathione reduction potential

https://doi.org/10.1016/j.redox.2022.102244Get rights and content
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Highlights

  • Oxidized but not reduced PDI promotes platelet aggregation.

  • Ero1α and PDI constitute an electron transport pathway on platelet surface.

  • Ero1α and PDI provide a redox environment optimal for platelet aggregation.

  • The functional interplay between Ero1α and PDI can be a new target for antiplatelet therapy.

Abstract

Protein disulfide isomerase (PDI), an oxidoreductase, possesses two vicinal cysteines in the -Cys-Gly-His-Cys-motif that either form a disulfide bridge (S–S) or exist in a sulfhydryl form (-SH), forming oxidized or reduced PDI, respectively. PDI has been proven to be critical for platelet aggregation, thrombosis, and hemostasis, and PDI inhibition is being evaluated as a novel antithrombotic strategy. The redox states of functional PDI during the regulation of platelet aggregation, however, remain to be elucidated. Endoplasmic reticulum (ER) oxidoreductin-1α (Ero1α) and PDI constitute the pivotal oxidative folding pathway in the ER and play an important role in ER redox homeostasis. Whether Ero1α and PDI constitute an extracellular electron transport pathway to mediate platelet aggregation is an open question. Here, we found that oxidized but not reduced PDI promotes platelet aggregation. On the platelet surface, Ero1α constitutively oxidizes PDI and further regulates platelet aggregation in a glutathione-dependent manner. The Ero1α/PDI system oxidizes reduced glutathione (GSH) and establishes a reduction potential optimal for platelet aggregation. Therefore, platelet aggregation is mediated by the Ero1α-PDI-GSH electron transport system on the platelet surface. We further showed that targeting the functional interplay between PDI and Ero1α by small molecule inhibitors may be a novel strategy for antithrombotic therapy.

Keywords

PDI
Ero1α
Platelet
Glutathione
Redox

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