Coagulation factor VIIa binds to herpes simplex virus 1-encoded glycoprotein C forming a factor X-enhanced tenase complex oriented on membranes.
coagulation factor
enzyme kinetics
enzyme mechanism
herpesvirus
tissue factor
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
03
09
2019
revised:
28
01
2020
accepted:
04
03
2020
pubmed:
8
3
2020
medline:
15
5
2021
entrez:
8
3
2020
Statut:
ppublish
Résumé
The cell membrane-derived initiators of coagulation, tissue factor (TF) and anionic phospholipid (aPL), are constitutive on the herpes simplex virus type 1 (HSV1) surface, bypassing physiological regulation. TF and aPL accelerate proteolytic activation of factor (F) X to FXa by FVIIa to induce clot formation and cell signaling. Thus, infection in vivo is enhanced by virus surface TF. HSV1-encoded glycoprotein C (gC) is implicated in this tenase activity by providing viral FX binding sites and increasing FVIIa function in solution. To examine the biochemical influences of gC on FVIIa-dependent FX activation. Immunogold electron microscopy (IEM), kinetic chromogenic assays and microscale thermophoresis were used to dissect tenase biochemistry. Recombinant TF and gC were solubilized (s) by substituting the transmembrane domain with poly-histidine, which could be orientated on synthetic unilamellar vesicles containing Ni-chelating lipid (Ni-aPL). These constructs were compared to purified HSV1 TF±/gC ± variants. IEM confirmed that gC, TF, and aPL are simultaneously expressed on a single HSV1 particle where the contribution of gC to tenase activity required the availability of viral TF. Unlike viral tenase activity, the cofactor effects of sTF and sgC on FVIIa was additive when bound to Ni-aPL. FVIIa was found to bind to sgC and this was enhanced by FX. Orientation of sgC on a lipid membrane was critical for FVIIa-dependent FX activation. The assembly of gC with FVIIa/FX parallels that of TF and may involve other constituents on the HSV1 envelope with implications in virus infection and pathology.
Sections du résumé
BACKGROUND
The cell membrane-derived initiators of coagulation, tissue factor (TF) and anionic phospholipid (aPL), are constitutive on the herpes simplex virus type 1 (HSV1) surface, bypassing physiological regulation. TF and aPL accelerate proteolytic activation of factor (F) X to FXa by FVIIa to induce clot formation and cell signaling. Thus, infection in vivo is enhanced by virus surface TF. HSV1-encoded glycoprotein C (gC) is implicated in this tenase activity by providing viral FX binding sites and increasing FVIIa function in solution.
OBJECTIVE
To examine the biochemical influences of gC on FVIIa-dependent FX activation.
METHODS
Immunogold electron microscopy (IEM), kinetic chromogenic assays and microscale thermophoresis were used to dissect tenase biochemistry. Recombinant TF and gC were solubilized (s) by substituting the transmembrane domain with poly-histidine, which could be orientated on synthetic unilamellar vesicles containing Ni-chelating lipid (Ni-aPL). These constructs were compared to purified HSV1 TF±/gC ± variants.
RESULTS
IEM confirmed that gC, TF, and aPL are simultaneously expressed on a single HSV1 particle where the contribution of gC to tenase activity required the availability of viral TF. Unlike viral tenase activity, the cofactor effects of sTF and sgC on FVIIa was additive when bound to Ni-aPL. FVIIa was found to bind to sgC and this was enhanced by FX. Orientation of sgC on a lipid membrane was critical for FVIIa-dependent FX activation.
CONCLUSIONS
The assembly of gC with FVIIa/FX parallels that of TF and may involve other constituents on the HSV1 envelope with implications in virus infection and pathology.
Identifiants
pubmed: 32145149
doi: 10.1111/jth.14790
pmc: PMC7647453
mid: NIHMS1576115
pii: S1538-7836(22)01425-8
doi:
Substances chimiques
Neoplasm Proteins
0
Viral Envelope Proteins
0
glycoprotein gC, herpes simplex virus type 1
0
Factor X
9001-29-0
Thromboplastin
9035-58-9
Factor VIIa
EC 3.4.21.21
Cysteine Endopeptidases
EC 3.4.22.-
cancer procoagulant
EC 3.4.22.26
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1370-1380Subventions
Organisme : NHLBI NIH HHS
ID : R35 HL135823
Pays : United States
Organisme : CIHR
ID : 273985
Pays : Canada
Organisme : NIH HHS
ID : HL135823
Pays : United States
Informations de copyright
© 2020 International Society on Thrombosis and Haemostasis.
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