- Factor VII-activating protease
- Unraveling the release and regulation of dead cell nuclear damps
S.M. van Ham
- Award date
- 12 January 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Upon inflammation, uncleared dying cells are an important source of pro-inflammatory damage-associated molecular patterns (DAMPs). Major DAMPs are histones and double-stranded DNA, which together form chromatin. Factor VII-activating protease (FSAP) is activated upon contact with dead cells, and its proteolytic activity results in the release of chromatin from late apoptotic cells. In this thesis we studied the role of FSAP in the release of chromatin from dead cells and the regulation of extracellular DAMPs. We identified that FSAP not only liberates chromatin from late apoptotic cells, but in cooperation with DNase I also releases chromatin from necrotic cells. FSAP-mediated chromatin release from late apoptotic cells was impaired in serum from a subset of systemic lupus erythematosus patients. Dead cells induce the activation of FSAP, and we deduced that histones and RNA are likely the structures responsible for this activation. DNA-free histones are cytotoxic, but were efficiently degraded by activated FSAP. Histones within nucleosomes lacked cytotoxicity and did not induce FSAP activation. Notably, we detected nucleosomes and not DNA-free histones in sera of septic baboons and meningococcal disease patients. Not only histones, but the DAMP high mobility group box 1 protein (HMGB1) was also found to be degraded by active FSAP, although it did not induce activation of FSAP. We envisage an important role for FSAP in the release of chromatin from uncleared dying cells and in the degradation of histones and HMGB1. These functions suggest an important role for FSAP in the regulation of DAMP-mediated inflammation upon extensive cell death.
Thesis (complete) (Embargo up to and including 12 January 2019)
Chapter 5: DNA and Factor VII-activating protease protect against the cytotoxicity of histones (Embargo up to and including 12 January 2019)
Chapter 6: Factor VII-activating protease mediates the degradation of HMGB1 (Embargo up to and including 12 January 2019)
Chapter 7: Cellular RNA and histones play synergistic but distinct roles in FSAP activation induced by dead cells in serum (Embargo up to and including 12 January 2019)
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library, or send a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.