Cell-Free DNA Promotes Thrombin Autolysis and Generation of Thrombin-Derived C-Terminal Fragments
(2021) In Frontiers in Immunology 12.- Abstract
Cell-free DNA (cfDNA) is the major structural component of neutrophil extracellular traps (NETs), an innate immune response to infection. Antimicrobial proteins and peptides bound to cfDNA play a critical role in the bactericidal property of NETs. Recent studies have shown that NETs have procoagulant activity, wherein cfDNA triggers thrombin generation through activation of the intrinsic pathway of coagulation. We have recently shown that thrombin binds to NETs in vitro and consequently can alter the proteome of NETs. However, the effect of NETs on thrombin is still unknown. In this study, we report that DNA binding leads to thrombin autolysis and generation of multiple thrombin-derived C-terminal peptides (TCPs) in vitro. Employing a... (More)
Cell-free DNA (cfDNA) is the major structural component of neutrophil extracellular traps (NETs), an innate immune response to infection. Antimicrobial proteins and peptides bound to cfDNA play a critical role in the bactericidal property of NETs. Recent studies have shown that NETs have procoagulant activity, wherein cfDNA triggers thrombin generation through activation of the intrinsic pathway of coagulation. We have recently shown that thrombin binds to NETs in vitro and consequently can alter the proteome of NETs. However, the effect of NETs on thrombin is still unknown. In this study, we report that DNA binding leads to thrombin autolysis and generation of multiple thrombin-derived C-terminal peptides (TCPs) in vitro. Employing a 25-residue prototypic TCP, GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), we show that TCPs bind NETs, thus conferring mutual protection against nuclease and protease degradation. Together, our results demonstrate the complex interplay between coagulation, NET formation, and thrombin cleavage and identify a previously undisclosed mechanism for formation of TCPs.
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- author
- Saravanan, Rathi ; Choong, Yeu Khai ; Lim, Chun Hwee LU ; Lim, Li Ming ; Petrlova, Jitka LU and Schmidtchen, Artur LU
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- antimicrobial peptides, cell-free DNA (cfDNA), coagulation, host defense peptides, molecular innate immunity, NETs (neutrophil extracellular traps), thrombin
- in
- Frontiers in Immunology
- volume
- 12
- article number
- 593020
- publisher
- Frontiers Media S. A.
- external identifiers
-
- pmid:33717072
- scopus:85102339869
- ISSN
- 1664-3224
- DOI
- 10.3389/fimmu.2021.593020
- language
- English
- LU publication?
- yes
- id
- f6e35e4b-7b36-4ab4-acb7-52364fbd46af
- date added to LUP
- 2021-03-26 08:06:43
- date last changed
- 2024-06-29 09:42:30
@article{f6e35e4b-7b36-4ab4-acb7-52364fbd46af, abstract = {{<p>Cell-free DNA (cfDNA) is the major structural component of neutrophil extracellular traps (NETs), an innate immune response to infection. Antimicrobial proteins and peptides bound to cfDNA play a critical role in the bactericidal property of NETs. Recent studies have shown that NETs have procoagulant activity, wherein cfDNA triggers thrombin generation through activation of the intrinsic pathway of coagulation. We have recently shown that thrombin binds to NETs in vitro and consequently can alter the proteome of NETs. However, the effect of NETs on thrombin is still unknown. In this study, we report that DNA binding leads to thrombin autolysis and generation of multiple thrombin-derived C-terminal peptides (TCPs) in vitro. Employing a 25-residue prototypic TCP, GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), we show that TCPs bind NETs, thus conferring mutual protection against nuclease and protease degradation. Together, our results demonstrate the complex interplay between coagulation, NET formation, and thrombin cleavage and identify a previously undisclosed mechanism for formation of TCPs.</p>}}, author = {{Saravanan, Rathi and Choong, Yeu Khai and Lim, Chun Hwee and Lim, Li Ming and Petrlova, Jitka and Schmidtchen, Artur}}, issn = {{1664-3224}}, keywords = {{antimicrobial peptides; cell-free DNA (cfDNA); coagulation; host defense peptides; molecular innate immunity; NETs (neutrophil extracellular traps); thrombin}}, language = {{eng}}, publisher = {{Frontiers Media S. A.}}, series = {{Frontiers in Immunology}}, title = {{Cell-Free DNA Promotes Thrombin Autolysis and Generation of Thrombin-Derived C-Terminal Fragments}}, url = {{http://dx.doi.org/10.3389/fimmu.2021.593020}}, doi = {{10.3389/fimmu.2021.593020}}, volume = {{12}}, year = {{2021}}, }