Stabilin-2 is a clearance receptor for multiple procoagulant plasma ligands Short title: Stabilin-2 plasma ligands

ABSTRACT: Damaging STAB2 gene variants are associated with increased venous thromboembolic risk. STAB2 encodes stabilin-2, a clearance receptor, expressed by the liver and spleen. Given its function, it is likely that the prothrombotic state associated with stabilin-2 deficiency is due to reduced procoagulant protein clearance, but the identity of these ligands is unknown. We aimed to identify plasma stabilin-2 ligands using proximity biotinylation proteomics. Cells stably expressing stabilin-2-TurboID were incubated with human plasma and biotin to initiate TurboID labeling of plasma ligands in endocytic vesicles. Biotinylated proteins were purified and identified using mass spectrometry. Candidate plasma ligands with roles in hemostasis were fluorescently labeled and incubated with stabilin-2 expressing and control cells. Flow cytometry assessed ligand surface binding and confocal microcopy assessed colocalization with stabilin-2 and lysosomes. Furthermore, plasma levels of these ligands were measured in Stab2 deficient mice and littermate controls. Twenty-eight stabilin-2 specific ligands were identified. Interactions with von Willebrand factor (VWF), fibrinogen, pro(thrombin), heparin cofactor II (HCII), high molecular weight kininogen (HMWK), plasminogen and C4b binding protein (C4bp) were probed. HCII, HMWK, plasminogen and fibrinogen showed binding to stabilin-2 using flow cytometry (>2-fold higher than controls). Confocal microscopy demonstrated stabilin-2 dependent colocalization of all ligands with lysosomes. In Stab2 deficient mice, ligand levels were not significantly higher than wild type, suggesting in mice stabilin-2 is not their main clearance receptor. These results confirm the value of proximity labeling proteomics in identifying receptor ligands and suggest damaging STAB2 variants increase venous thromboembolic risk through altered clearance of hemostatic proteins.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Early Embryonic Cell

DISEASE(S): Thrombosis

SUBMITTER: Karl Desch  

LAB HEAD: Karl Desch

PROVIDER: PXD055782 | Pride | 2026-03-30

REPOSITORIES: Pride