Abstract
Extracellular pools of intracellular molecular chaperones are increasingly evident. The peri/epicellular(pec) pool of the endoplasmic reticulum redox chaperone protein disulfide isomerase-A1(PDI) is involved in thrombosis and vascular remodeling, while PDI externalization routes remain elusive. In endothelial cells, vesicular-type PDI secretion involves classical and unconventional pathways, while in platelets PDI exocytosis involves actin cytoskeleton. However, little is known about pecPDI in vascular smooth muscle cells(VSMC). Here, we showed that VSMC display a robust cell-surface(cs) PDI pool, which binds to cs independently of electrostatic forces. However, contrarily to other cells, soluble secreted PDI pool was undetectable in VSMC. Calcium ionophore A23187 and TNFα enhanced VSMC csPDI. Furthermore, VSMC PDI externalization occurred via Golgi-bypass unconventional route, which was independent of cytoskeleton or lysosomes. Secreted PDI was absent in ex vivo wild-type mice aortas but markedly enhanced in PDI-overexpressing mice. Such characterization of VSMC pecPDI reinforces cell-type and context specific routes of PDI externalization.
Highlights
Molecular chaperones from the cytosol or endoplasmic reticulum (ER) are known to be externalizated in many cell types, such as immune cells [1,2], tumor cells [3], hepatocytes, pancreatic cells, platelets and endothelial cells (EC) [4]
As the role of proinflammatory cytokines in PDI externalization in vascular smooth muscle cell (VSMC) is unknown, we examined the effects of tumor necrosis factor α (TNFα) incubation on cell-surface PDI (csPDI) levels
Vascular-related physiological roles of peri/epicellular PDI (pecPDI) are less explored, though we described that pecPDI mediates alpha5 integrin oxidation in EC submitted to physiological levels of laminar arterial shear stress [8]
Summary
Molecular chaperones from the cytosol or endoplasmic reticulum (ER) are known to be externalizated in many cell types, such as immune cells [1,2], tumor cells [3], hepatocytes, pancreatic cells, platelets and endothelial cells (EC) [4]. Some pecPDI-associated functions include: a) disulfide bond reduction of HIV glycoprotein gp120, tumor endothelial marker-5, αvβ integrins, tissue factor, αMβ2 and β1 integrin [6]; b) dithiol oxidation of alpha integrin [8] and c) thiol-disulfide isomerization of ADAM17 and αIIbβ3 [6] Such effects associate with pecPDI-mediated regulation of viral infection [9,10], platelet activation [11,12], thrombosis [7,13,14] and expansive vascular remodeling [15]. PecPDI inhibition is increasingly investigated as a novel promising anti-thrombotic strategy [16], through cell-impermeable compounds that target PDI b'x or b' substrate-binding domains [17,18], while targetting of the redox-active a' domain has an attractive anti-thrombotic potential [19,20] Such pecPDI implications enhanced the interest to understand PDI externalization routes across distinct cell types, which remain elusive so far.
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