title: Thioredoxin and thioredoxin reductase control tissue factor activity by thiol redox-dependent mechanism.
abstract: Abnormally enhanced tissue factor (TF) activity is related to increased thrombosis risk in which oxidative stress plays a critical role. Human cytosolic thioredoxin (hTrx1) and thioredoxin reductase (TrxR), also secreted into circulation, have the power to protect against oxidative stress. However, the relationship between hTrx1/TrxR and TF remains unknown. Here we show reversible association of hTrx1 with TF in human serum and plasma samples. The association is dependent on hTrx1-Cys-73 that bridges TF-Cys-209 via a disulfide bond. hTrx1-Cys-73 is absolutely required for hTrx1 to interfere with FVIIa binding to purified and cell-surface TF, consequently suppressing TF-dependent procoagulant activity and proteinase-activated receptor-2 activation. Moreover, hTrx1/TrxR plays an important role in sensing the alterations of NADPH/NADP(+) states and transducing this redox-sensitive signal into changes in TF activity. With NADPH, hTrx1/TrxR readily facilitates the reduction of TF, causing a decrease in TF activity, whereas with NADP(+), hTrx1/TrxR promotes the oxidation of TF, leading to an increase in TF activity. By comparison, TF is more likely to favor the reduction by hTrx1-TrxR-NADPH. This reversible reduction-oxidation reaction occurs in the TF extracellular domain that contains partially opened Cys-49/-57 and Cys-186/-209 disulfide bonds. The cell-surface TF procoagulant activity is significantly increased after hTrx1-knockdown. The response of cell-surface TF procoagulant activity to H(2)O(2) is efficiently suppressed through elevating cellular TrxR activity via selenium supplementation. Our data provide a novel mechanism for redox regulation of TF activity. By modifying Cys residues or regulating Cys redox states in TF extracellular domain, hTrx1/TrxR function as a safeguard against inappropriate TF activity.
authors.affiliation: College of Life Sciences, University of Chinese Academy of Sciences, 100049 Beijing, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wu
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Ma
authors.forename: Liangwei
authors.initials: L
authors.lastname: Zhong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D015942:Factor VIIa / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011485:Protein Binding; D044464:Receptor, PAR-2 / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism*; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D004220:Disulfides; D044464:Receptor, PAR-2; D013438:Sulfhydryl Compounds; C491203:TXN protein, human; D013879:Thioredoxins; D013925:Thromboplastin; D013880:Thioredoxin-Disulfide Reductase; D015942:Factor VIIa; D003545:Cysteine