The scavenger receptor SCARA5 is an endocytic receptor for von Willebrand factor expressed by littoral cells in the human spleen

Abstract

Background: Scavenger receptors play a significant role in clearing aged proteins from the plasma, including the large glycoprotein coagulation factors von Willebrand factor (VWF) and factor VIII (FVIII). A large genome-wide association study metaanalysis has identified genetic variants in the gene SCARA5, which encodes the class A scavenger receptor SCARA5, as being associated with plasma levels of VWF and FVIII.Objectives: The ability of SCARA5 to regulate the clearance of VWF-FVIII was characterized.Methods: VWF-FVIII interactions with SCARA5 were evaluated by solid phase binding assays and in vitro cell based assays. The influence of SCARA5 deficiency on VWF:Ag and half-life was assessed in a murine model. The expression pattern of SCARA5 and its colocalization with VWF was evaluated in human tissues.Results: VWF and the VWF-FVIII complex bound to human recombinant SCARA5 in a dose-and calcium-dependent manner. SCARA5 expressing HEK 293T cells bound and internalized VWF and the VWF-FVIII complex into early endosomes. In vivo, SCARA5 deficiency had a modest influence on the half-life of human VWF. mRNA analysis and immunohistochemistry determined that human SCARA5 is expressed in kidney podocytes and the red pulp, white pulp, and marginal zone of the spleen.VWF was found to colocalize with SCARA5 expressed by littoral cells lining the red pulp of the human spleen.Conclusions: SCARA5 is an adhesive and endocytic receptor for VWF. In human tissues, SCARA5 is expressed by kidney podocytes and splenic littoral endothelial cells. SCARA5 may have a modest influence on VWF clearance in humans. K E Y W O R D Sendocytosis, endothelial cells, factor VIII, GWAS, receptors scavenger, von Willebrand factor | 1385 SWYSTUN eT al.

Targeting von Willebrand factor in liver diseases: A novel therapeutic strategy?

“…17 Recently, it was shown that the macrophage galactose-type lectin receptor also regulates VWF clearance in a sialic acid-dependent manner. 18 In addition, several other specific lectin receptors (including sialic acid-binding immunoglobulin-like Lectin 5 19 and C-type lectin domain family 4 member M) 20 and scavenger receptors (including low-density lipoprotein receptor-related protein-1, 21 scavenger receptor A1, 22 scavenger receptor class A member 5, 23 and stabilin-2) 24 have been shown to participate in VWF clearance.…”

Factor VIII pharmacokinetics associates with genetic modifiers of VWF and FVIII clearance in an adult hemophilia A population

“…16,17 Confirmatory studies using animal models, cell-based studies, and ligand-receptor binding assays have confirmed that CLEC4M, SCARA5, and stabilin-2 are capable of binding and internalizing the human VWF protein or the VWF-FVIII complex. [18][19][20] Variants in these receptors may therefore modify the PK profile of FVIII.…”

FVIII at the crossroad of coagulation, bone and immune biology: Emerging evidence of biological activities beyond hemostasis

“…SCARA-5 was co-localized with VWF and can bind and internalize this factor alone or in a complex with FVIII. The binding and internalization of FVIII to SCARA-5 cannot occur in the absence of VWF [142]. SCARA-5 is expressed by osteoblastic like cells and inhibits their proliferation [143].…”