The role of histidine-rich glycoprotein in necrotic cell clearance and regulation of degradative enzymes
Abstract
Histidine-rich glycoprotein (HRG) is an abundant multi-functional protein that is present in the plasma of many vertebrates. HRG has a multi-domain structure that allows the molecule to interact with many ligands including heparin, heparan sulfate (HS), Fcy
receptors (FcyR), plasminogen, fibrinogen, IgG, Clq, haem and Zn2+. The ability of
HRG to interact with various ligands simultaneously has suggested that HRG can act as an adaptor molecule and regulate numerous biological processes such as immune
complex/necrotic cell/pathogen clearance, cell adhesion, angiogenesis, coagulation and
fibrinolysis. Although HRG is thought to play an important role in both immunity and
vascular biology, the molecular mechanisms underpinning its action remain largely
undefined. Thus, the aim of this thesis was to characterize the molecular components
that are involved in HRG-mediated uptake of necrotic cells and to further examine the
role of HRG in regulating degradative enzymes, such as plasminogen/plasmin and
heparanase...In summary, the studies presented in this thesis have delineated the molecular mechanisms underlying necrotic cell removal mediated by plasma-derived HRG and may have important implications for the development of autoimmune disease caused by
defective clearance of dying/dead cells. In addition, the ability of HRG to regulate
degradative enzymes, such as plasmin and heparanase, further supports the view that
HRG may play an important role in angiogenesis, leukocyte migration and cancer
metastasis.