Semin Thromb Hemost 2015; 41(07): 765-773
DOI: 10.1055/s-0035-1564047
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Protein Disulfide Isomerase in Thrombosis

Joyce Chiu
1   ACRF-Centenary Cancer Research Centre & NHMRC Clinical Trials Centre, University of Sydney, New South Wales, Australia
,
Freda Passam
2   St George Clinical School, St George Hospital, Kogarah, New South Wales, Australia
,
Diego Butera
1   ACRF-Centenary Cancer Research Centre & NHMRC Clinical Trials Centre, University of Sydney, New South Wales, Australia
,
Philip J. Hogg
1   ACRF-Centenary Cancer Research Centre & NHMRC Clinical Trials Centre, University of Sydney, New South Wales, Australia
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Publikationsverlauf

Publikationsdatum:
26. September 2015 (online)

Abstract

Protein disulfide isomerase (PDI) is a 57-kDa oxidoreductase that facilitates cysteine thiol reactions inside and outside the cell. It mediates reduction or oxidation of protein disulfide bonds, thiol/disulfide exchange reactions, and transfer of NO from one protein thiol to another. It also has chaperone properties. PDI is actively secreted by most, if not all, of the cell types involved in thrombosis, binds to integrins on the cell surface, and circulates as a soluble protein in blood. It plays a critical role in thrombosis in mice and presumably the same role in human thrombosis. Eight proteins involved in thrombosis have been identified as PDI substrates; however, the role of this oxidoreductase in this process is not fully understood. Novel small-molecule PDI inhibitors have been developed and are being evaluated as antithrombotics in clinical trials. This combination of ongoing laboratory and clinical studies will greatly accelerate the pace of discovery and targeting of PDI function in thrombosis.

 
  • References

  • 1 Wang C, Li W, Ren J , et al. Structural insights into the redox-regulated dynamic conformations of human protein disulfide isomerase. Antioxid Redox Signal 2013; 19 (1) 36-45
  • 2 Puig A, Gilbert HF. Protein disulfide isomerase exhibits chaperone and anti-chaperone activity in the oxidative refolding of lysozyme. J Biol Chem 1994; 269 (10) 7764-7771
  • 3 Lu J, Holmgren A. The thioredoxin superfamily in oxidative protein folding. Antioxid Redox Signal 2014; 21 (3) 457-470
  • 4 Ramachandran N, Root P, Jiang XM, Hogg PJ, Mutus B. Mechanism of transfer of NO from extracellular S-nitrosothiols into the cytosol by cell-surface protein disulfide isomerase. Proc Natl Acad Sci U S A 2001; 98 (17) 9539-9544
  • 5 Zai A, Rudd MA, Scribner AW, Loscalzo J. Cell-surface protein disulfide isomerase catalyzes transnitrosation and regulates intracellular transfer of nitric oxide. J Clin Invest 1999; 103 (3) 393-399
  • 6 Pihlajaniemi T, Helaakoski T, Tasanen K , et al. Molecular cloning of the beta-subunit of human prolyl 4-hydroxylase. This subunit and protein disulphide isomerase are products of the same gene. EMBO J 1987; 6 (3) 643-649
  • 7 Wetterau JR, Combs KA, Spinner SN, Joiner BJ. Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex. J Biol Chem 1990; 265 (17) 9800-9807
  • 8 Sobierajska K, Skurzynski S, Stasiak M, Kryczka J, Cierniewski CS, Swiatkowska M. Protein disulfide isomerase directly interacts with β-actin Cys374 and regulates cytoskeleton reorganization. J Biol Chem 2014; 289 (9) 5758-5773
  • 9 Munro S, Pelham HR. A C-terminal signal prevents secretion of luminal ER proteins. Cell 1987; 48 (5) 899-907
  • 10 Wan SW, Lin CF, Lu YT, Lei HY, Anderson R, Lin YS. Endothelial cell surface expression of protein disulfide isomerase activates β1 and β3 integrins and facilitates dengue virus infection. J Cell Biochem 2012; 113 (5) 1681-1691
  • 11 Dorner AJ, Wasley LC, Raney P, Haugejorden S, Green M, Kaufman RJ. The stress response in Chinese hamster ovary cells. Regulation of ERp72 and protein disulfide isomerase expression and secretion. J Biol Chem 1990; 265 (35) 22029-22034
  • 12 Jiang XM, Fitzgerald M, Grant CM, Hogg PJ. Redox control of exofacial protein thiols/disulfides by protein disulfide isomerase. J Biol Chem 1999; 274 (4) 2416-2423
  • 13 Rose JK, Doms RW. Regulation of protein export from the endoplasmic reticulum. Annu Rev Cell Biol 1988; 4: 257-288
  • 14 Thon JN, Peters CG, Machlus KR , et al. T granules in human platelets function in TLR9 organization and signaling. J Cell Biol 2012; 198 (4) 561-574
  • 15 Jasuja R, Furie B, Furie BC. Endothelium-derived but not platelet-derived protein disulfide isomerase is required for thrombus formation in vivo. Blood 2010; 116 (22) 4665-4674
  • 16 Sharda A, Kim SH, Jasuja R , et al. Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome. Blood 2015; 125 (10) 1633-1642
  • 17 Hotchkiss KA, Matthias LJ, Hogg PJ. Exposure of the cryptic Arg-Gly-Asp sequence in thrombospondin-1 by protein disulfide isomerase. Biochim Biophys Acta 1998; 1388 (2) 478-488
  • 18 Chen K, Lin Y, Detwiler TC. Protein disulfide isomerase activity is released by activated platelets. Blood 1992; 79 (9) 2226-2228
  • 19 Chen K, Detwiler TC, Essex DW. Characterization of protein disulphide isomerase released from activated platelets. Br J Haematol 1995; 90 (2) 425-431
  • 20 Bennett TA, Edwards BS, Sklar LA, Rogelj S. Sulfhydryl regulation of L-selectin shedding: phenylarsine oxide promotes activation-independent L-selectin shedding from leukocytes. J Immunol 2000; 164 (8) 4120-4129
  • 21 Kröning H, Kähne T, Ittenson A, Franke A, Ansorge S. Thiol-proteindisulfide-oxidoreductase (proteindisulfide isomerase): a new plasma membrane constituent of mature human B lymphocytes. Scand J Immunol 1994; 39 (4) 346-350
  • 22 Stantchev TS, Paciga M, Lankford CR, Schwartzkopff F, Broder CC, Clouse KA. Cell-type specific requirements for thiol/disulfide exchange during HIV-1 entry and infection. Retrovirology 2012; 9: 97
  • 23 Kallakunta VM, Slama-Schwok A, Mutus B. Protein disulfide isomerase may facilitate the efflux of nitrite derived S-nitrosothiols from red blood cells. Redox Biol 2013; 1: 373-380
  • 24 Swiatkowska M, Szymański J, Padula G, Cierniewski CS. Interaction and functional association of protein disulfide isomerase with alphaVbeta3 integrin on endothelial cells. FEBS J 2008; 275 (8) 1813-1823
  • 25 Cho J, Kennedy DR, Lin L , et al. Protein disulfide isomerase capture during thrombus formation in vivo depends on the presence of β3 integrins. Blood 2012; 120 (3) 647-655
  • 26 Farrah T, Deutsch EW, Omenn GS , et al. A high-confidence human plasma proteome reference set with estimated concentrations in PeptideAtlas. Mol Cell Proteomics 2011; 10 (9) 006353
  • 27 Burgess JK, Hotchkiss KA, Suter C , et al. Physical proximity and functional association of glycoprotein 1balpha and protein-disulfide isomerase on the platelet plasma membrane. J Biol Chem 2000; 275 (13) 9758-9766
  • 28 Löw H, Crane FL, Morré DJ. Putting together a plasma membrane NADH oxidase: a tale of three laboratories. Int J Biochem Cell Biol 2012; 44 (11) 1834-1838
  • 29 Swiatkowska M, Padula G, Michalec L, Stasiak M, Skurzynski S, Cierniewski CS. Ero1alpha is expressed on blood platelets in association with protein-disulfide isomerase and contributes to redox-controlled remodeling of alphaIIbbeta3. J Biol Chem 2010; 285 (39) 29874-29883
  • 30 Gardiner EE, Andrews RK. Structure and function of platelet receptors initiating blood clotting. Adv Exp Med Biol 2014; 844: 263-275
  • 31 Lahav J, Gofer-Dadosh N, Luboshitz J, Hess O, Shaklai M. Protein disulfide isomerase mediates integrin-dependent adhesion. FEBS Lett 2000; 475 (2) 89-92
  • 32 Lahav J, Jurk K, Hess O , et al. Sustained integrin ligation involves extracellular free sulfhydryls and enzymatically catalyzed disulfide exchange. Blood 2002; 100 (7) 2472-2478
  • 33 Manickam N, Sun X, Hakala KW, Weintraub ST, Essex DW. Thiols in the alphaIIbbeta3 integrin are necessary for platelet aggregation. Br J Haematol 2008; 142 (3) 457-465
  • 34 Lahav J, Wijnen EM, Hess O , et al. Enzymatically catalyzed disulfide exchange is required for platelet adhesion to collagen via integrin alpha2beta1. Blood 2003; 102 (6) 2085-2092
  • 35 Bertling A, Niemann S, Hussain M , et al. Staphylococcal extracellular adherence protein induces platelet activation by stimulation of thiol isomerases. Arterioscler Thromb Vasc Biol 2012; 32 (8) 1979-1990
  • 36 Cho J, Furie BC, Coughlin SR, Furie B. A critical role for extracellular protein disulfide isomerase during thrombus formation in mice. J Clin Invest 2008; 118 (3) 1123-1131
  • 37 Reinhardt C, von Brühl ML, Manukyan D , et al. Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. J Clin Invest 2008; 118 (3) 1110-1122
  • 38 Popescu NI, Lupu C, Lupu F. Extracellular protein disulfide isomerase regulates coagulation on endothelial cells through modulation of phosphatidylserine exposure. Blood 2010; 116 (6) 993-1001
  • 39 Muller C, Bandemer J, Vindis C , et al. Protein disulfide isomerase modification and inhibition contribute to ER stress and apoptosis induced by oxidized low density lipoproteins. Antioxid Redox Signal 2013; 18 (7) 731-742
  • 40 Kim K, Hahm E, Li J , et al. Platelet protein disulfide isomerase is required for thrombus formation but not for hemostasis in mice. Blood 2013; 122 (6) 1052-1061
  • 41 Langer F, Ruf W. Synergies of phosphatidylserine and protein disulfide isomerase in tissue factor activation. Thromb Haemost 2014; 111 (4) 590-597
  • 42 Ahamed J, Versteeg HH, Kerver M , et al. Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc Natl Acad Sci U S A 2006; 103 (38) 13932-13937
  • 43 Furlan-Freguia C, Marchese P, Gruber A, Ruggeri ZM, Ruf W. P2×7 receptor signaling contributes to tissue factor-dependent thrombosis in mice. J Clin Invest 2011; 121 (7) 2932-2944
  • 44 Langer F, Spath B, Fischer C , et al. Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase. Blood 2013; 121 (12) 2324-2335
  • 45 Lysov Z, Swystun LL, Kuruvilla S, Arnold A, Liaw PC. Lung cancer chemotherapy agents increase procoagulant activity via protein disulfide isomerase-dependent tissue factor decryption. Blood Coagul Fibrinolysis 2015; 26 (1) 36-45
  • 46 Hahm E, Li J, Kim K, Huh S, Rogelj S, Cho J. Extracellular protein disulfide isomerase regulates ligand-binding activity of αMβ2 integrin and neutrophil recruitment during vascular inflammation. Blood 2013; 121 (19) 3789-3800 , S1–S15
  • 47 Essex DW, Li M, Miller A, Feinman RD. Protein disulfide isomerase and sulfhydryl-dependent pathways in platelet activation. Biochemistry 2001; 40 (20) 6070-6075
  • 48 Sweetwyne MT, Murphy-Ullrich JE. Thrombospondin1 in tissue repair and fibrosis: TGF-β-dependent and independent mechanisms. Matrix Biol 2012; 31 (3) 178-186
  • 49 Speziale MV, Detwiler TC. Free thiols of platelet thrombospondin. Evidence for disulfide isomerization. J Biol Chem 1990; 265 (29) 17859-17867
  • 50 Sun X, Skorstengaard K, Mosher DF. Disulfides modulate RGD-inhibitable cell adhesive activity of thrombospondin. J Cell Biol 1992; 118 (3) 693-701
  • 51 Hogg PJ, Jiménez BM, Chesterman CN. Identification of possible inhibitory reactive centers in thrombospondin 1 that may bind cathepsin G and neutrophil elastase. Biochemistry 1994; 33 (21) 6531-6537
  • 52 Hogg PJ, Owensby DA, Chesterman CN. Thrombospondin 1 is a tight-binding competitive inhibitor of neutrophil cathepsin G. Determination of the kinetic mechanism of inhibition and localization of cathepsin G binding to the thrombospondin 1 type 3 repeats. J Biol Chem 1993; 268 (29) 21811-21818
  • 53 Hogg PJ, Owensby DA, Mosher DF, Misenheimer TM, Chesterman CN. Thrombospondin is a tight-binding competitive inhibitor of neutrophil elastase. J Biol Chem 1993; 268 (10) 7139-7146
  • 54 Misenheimer TM, Mosher DF. Calcium ion binding to thrombospondin 1. J Biol Chem 1995; 270 (4) 1729-1733
  • 55 Hogg PJ, Hotchkiss KA, Jiménez BM, Stathakis P, Chesterman CN. Interaction of platelet-derived growth factor with thrombospondin 1. Biochem J 1997; 326 (Pt 3) 709-716
  • 56 Hotchkiss KA, Chesterman CN, Hogg PJ. Catalysis of disulfide isomerization in thrombospondin 1 by protein disulfide isomerase. Biochemistry 1996; 35 (30) 9761-9767
  • 57 Milev Y, Essex DW. Protein disulfide isomerase catalyzes the formation of disulfide-linked complexes of thrombospondin-1 with thrombin-antithrombin III. Arch Biochem Biophys 1999; 361 (1) 120-126
  • 58 Mor-Cohen R. Disulfide Bonds as Regulators of Integrin Function in Thrombosis and Hemostasis. Antioxid Redox Signal 2014; ; Epub ahead of print
  • 59 Cook KM, Hogg PJ. Post-translational control of protein function by disulfide bond cleavage. Antioxid Redox Signal 2013; 18 (15) 1987-2015
  • 60 Metcalfe C, Cresswell P, Ciaccia L, Thomas B, Barclay AN. Labile disulfide bonds are common at the leucocyte cell surface. Open Biol 2011; 1 (3) 110010
  • 61 Zhu J, Luo BH, Xiao T, Zhang C, Nishida N, Springer TA. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol Cell 2008; 32 (6) 849-861
  • 62 Xiong JP, Mahalingham B, Alonso JL , et al. Crystal structure of the complete integrin alphaVbeta3 ectodomain plus an alpha/beta transmembrane fragment. J Cell Biol 2009; 186 (4) 589-600
  • 63 Mor-Cohen R, Rosenberg N, Einav Y , et al. Unique disulfide bonds in epidermal growth factor (EGF) domains of β3 affect structure and function of αIIbβ3 and αvβ3 integrins in different manner. J Biol Chem 2012; 287 (12) 8879-8891
  • 64 Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med 2013; 368 (11) 1033-1044
  • 65 Passam FH, Rahgozar S, Qi M , et al. Beta 2 glycoprotein I is a substrate of thiol oxidoreductases. Blood 2010; 116 (11) 1995-1997
  • 66 Ioannou Y, Zhang JY, Passam FH , et al. Naturally occurring free thiols within beta 2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress-induced cell injury. Blood 2010; 116 (11) 1961-1970
  • 67 Ioannou Y, Zhang JY, Qi M , et al. Novel assays of thrombogenic pathogenicity in the antiphospholipid syndrome based on the detection of molecular oxidative modification of the major autoantigen β2-glycoprotein I. Arthritis Rheum 2011; 63 (9) 2774-2782
  • 68 Chen VM, Hogg PJ. Allosteric disulfide bonds in thrombosis and thrombolysis. J Thromb Haemost 2006; 4 (12) 2533-2541
  • 69 Chen VM, Hogg PJ. Encryption and decryption of tissue factor. J Thromb Haemost 2013; 11 (Suppl. 01) 277-284
  • 70 Liang HP, Brophy TM, Hogg PJ. Redox properties of the tissue factor Cys186-Cys209 disulfide bond. Biochem J 2011; 437 (3) 455-460
  • 71 Chen VM, Ahamed J, Versteeg HH, Berndt MC, Ruf W, Hogg PJ. Evidence for activation of tissue factor by an allosteric disulfide bond. Biochemistry 2006; 45 (39) 12020-12028
  • 72 Hayano T, Inaka K, Otsu M , et al. PDI and glutathione-mediated reduction of the glutathionylated variant of human lysozyme. FEBS Lett 1993; 328 (1–2) 203-208
  • 73 van den Hengel LG, Osanto S, Reitsma PH, Versteeg HH. Murine tissue factor coagulant activity is critically dependent on the presence of an intact allosteric disulfide. Haematologica 2013; 98 (1) 153-158
  • 74 Giannakopoulos B, Gao L, Qi M , et al. Factor XI is a substrate for oxidoreductases: enhanced activation of reduced FXI and its role in antiphospholipid syndrome thrombosis. J Autoimmun 2012; 39 (3) 121-129
  • 75 Jin RC, Loscalzo J. Vascular Nitric Oxide: Formation and Function. J Blood Med 2010; 2010 (1) 147-162
  • 76 Hogg PJ. Disulfide bonds as switches for protein function. Trends Biochem Sci 2003; 28 (4) 210-214
  • 77 Schmidt B, Ho L, Hogg PJ. Allosteric disulfide bonds. Biochemistry 2006; 45 (24) 7429-7433
  • 78 Butera D, Cook KM, Chiu J, Wong JW, Hogg PJ. Control of blood proteins by functional disulfide bonds. Blood 2014; 123 (13) 2000-2007
  • 79 Hogg PJ. Targeting allosteric disulphide bonds in cancer. Nat Rev Cancer 2013; 13 (6) 425-431
  • 80 Schmidt B, Hogg PJ. Search for allosteric disulfide bonds in NMR structures. BMC Struct Biol 2007; 7: 49
  • 81 Wong JW, Hogg PJ. Analysis of disulfide bonds in protein structures. J Thromb Haemost 2010; 8: 2345
  • 82 Zhou B, Baldus IB, Li W, Edwards SA, Gräter F. Identification of allosteric disulfides from prestress analysis. Biophys J 2014; 107 (3) 672-681
  • 83 Baldus IB, Gräter F. Mechanical force can fine-tune redox potentials of disulfide bonds. Biophys J 2012; 102 (3) 622-629
  • 84 Wiita AP, Perez-Jimenez R, Walther KA , et al. Probing the chemistry of thioredoxin catalysis with force. Nature 2007; 450 (7166) 124-127
  • 85 Wiita AP, Ainavarapu SR, Huang HH, Fernandez JM. Force-dependent chemical kinetics of disulfide bond reduction observed with single-molecule techniques. Proc Natl Acad Sci U S A 2006; 103 (19) 7222-7227
  • 86 Li W, Gräter F. Atomistic evidence of how force dynamically regulates thiol/disulfide exchange. J Am Chem Soc 2010; 132 (47) 16790-16795
  • 87 Rafeedheen R, Bliden KP, Liu F, Tantry US, Gurbel PA. Novel antiplatelet agents in cardiovascular medicine. Curr Treat Options Cardiovasc Med 2015; 17 (6) 383
  • 88 Xu S, Sankar S, Neamati N. Protein disulfide isomerase: a promising target for cancer therapy. Drug Discov Today 2014; 19 (3) 222-240
  • 89 Zwicker JI. Unconventional approaches to the prevention of cancer associated thrombosis. Thromb Res 2014; 133 (Suppl. 02) S44-S48
  • 90 Jasuja R, Passam FH, Kennedy DR , et al. Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents. J Clin Invest 2012; 122 (6) 2104-2113
  • 91 Khodier C, VerPlank L, Nag PP , et al. Identification of ML359 as a small molecule inhibitor of protein disulfide isomerase. In: Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information (US); 2010
  • 92 Ben Khalaf N, De Muylder G, Ratnam J , et al. A high-throughput turbidometric assay for screening inhibitors of Leishmania major protein disulfide isomerase. J Biomol Screen 2011; 16 (5) 545-551
  • 93 Khan MM, Simizu S, Lai NS, Kawatani M, Shimizu T, Osada H. Discovery of a small molecule PDI inhibitor that inhibits reduction of HIV-1 envelope glycoprotein gp120. ACS Chem Biol 2011; 6 (3) 245-251
  • 94 Hoffstrom BG, Kaplan A, Letso R , et al. Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins. Nat Chem Biol 2010; 6 (12) 900-906
  • 95 Flaumenhaft R, Furie B, Zwicker JI. Therapeutic implications of protein disulfide isomerase inhibition in thrombotic disease. Arterioscler Thromb Vasc Biol 2015; 35 (1) 16-23
  • 96 Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993; 342 (8878) 1007-1011
  • 97 McCullough ML, Peterson JJ, Patel R, Jacques PF, Shah R, Dwyer JT. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am J Clin Nutr 2012; 95 (2) 454-464
  • 98 Kozlov G, Määttänen P, Thomas DY, Gehring K. A structural overview of the PDI family of proteins. FEBS J 2010; 277 (19) 3924-3936
  • 99 Holbrook LM, Watkins NA, Simmonds AD, Jones CI, Ouwehand WH, Gibbins JM. Platelets release novel thiol isomerase enzymes which are recruited to the cell surface following activation. Br J Haematol 2010; 148 (4) 627-637
  • 100 Holbrook LM, Sasikumar P, Stanley RG, Simmonds AD, Bicknell AB, Gibbins JM. The platelet-surface thiol isomerase enzyme ERp57 modulates platelet function. J Thromb Haemost 2012; 10 (2) 278-288
  • 101 Wang L, Wu Y, Zhou J , et al. Platelet-derived ERp57 mediates platelet incorporation into a growing thrombus by regulation of the αIIbβ3 integrin. Blood 2013; 122 (22) 3642-3650
  • 102 Jordan PA, Stevens JM, Hubbard GP , et al. A role for the thiol isomerase protein ERP5 in platelet function. Blood 2005; 105 (4) 1500-1507