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Cell-Free DNA Promotes Thrombin Autolysis and Generation of Thrombin-Derived C-Terminal Fragments

Saravanan, Rathi ; Choong, Yeu Khai ; Lim, Chun Hwee LU orcid ; Lim, Li Ming ; Petrlova, Jitka LU and Schmidtchen, Artur LU (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
; ; ; ; and
organization
publishing date
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
  • scopus:85102339869
  • pmid:33717072
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
2024-06-16 11:11:14
@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}},
}