Extracellular Thiol Isomerases and Their Role in Thrombus Formation

Sol Schulman, Pavan Bendapudi, Anish Sharda, Vivien Chen, Lola Bellido-Martin, Reema Jasuja, Barbara C. Furie, Robert Flaumenhaft, Bruce Furie

The mammalian endoplasmic reticulum houses a large family of twenty thioredoxin-like proteins of which protein disulfide isomerase (PDI) is the archetypal member. Although the PDI family is best known for its role in oxidative protein folding of secretory proteins in the endoplasmic reticulum, these thioredoxin-like proteins fulfill ever-expanding roles, both within the secretory pathway and beyond. Recent Advances: Secreted PDI family proteins have now been shown to serve a critical role in platelet thrombus formation and fibrin generation. Utilizing intravital microscopy to visualize thrombus formation in mice, we have demonstrated the presence of extracellular PDI antigen during thrombus formation following injury of the vascular wall. Inhibition of PDI abrogates thrombus formation in vivo (16,26,46,55). These observations have been extended to other PDI family members, including ERp57 (39,116,118,123) and ERp5 (77). The "vascular thiol isomerases" are those PDI family members secreted from platelets and/or endothelium (40): PDI, ERp57, ERp5, ERp72, ERp44, ERp29, TMX3. We focus here on PDI (16,46,55), ERp57 (39,116,118,123), and ERp5 (77), which have been implicated in thrombus formation in vivo. It would appear that a system of thiol isomerase redox catalysts has been highjacked from the endoplasmic reticulum to regulate thrombus formation in the vasculature. How this redox system is trafficked to and regulated at the cell surface, the identity of extracellular substrates, why so many thiol isomerases are required, and which thiol isomerase functions are necessary are critical unanswered questions in understanding the role of thiol isomerases in thrombus formation.