How Does Protein Disulfide Isomerase Get Into a Thrombus?
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Numerous studies have demonstrated a role for thiol isomerases (TI), such as protein disulfide isomerase (PDI), in thrombosis.1 Using antibodies, inhibitors, inactive recombinant proteins, and transgenic animals, several groups have convincingly shown that platelet and endothelial cell enzymes contribute to normal platelet activation and deposition at vascular lesions. On the basis of these data, anti-TI therapeutics are being developed for use in humans.2 Platelets and endothelial cells contain at least 7 thioredoxin-like TIs; some of which seem to have overlapping functions.3 PDI, ERp57, and ERp5 have been studied in the most detail. For PDI, it seems to be released into the vascular microenvironment and retained via interactions with β3 integrins.4 Although important for thrombosis, it is unclear what critical substrates are modified by these enzymes or how they get into the extracellular space. To address the second question, Crescente et al5 examined how 2 TIs, PDI and ERp57, are packaged into platelets and how they are released on platelet activation.
See accompanying article on page 1164
Normally, TIs are present in the lumen of the endoplasmic reticulum (ER) or of other compartments of the secretory pathway. They facilitate the reshuffling of disulfide bonds in …