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Abstract
Basolateral polymerization of cellular fibronectin (FN) into a meshwork drives endothelial cell (EC) polarity and vascular remodelling. However, mechanisms coordinating α5β1 integrin-mediated extracellular FN endocytosis and exocytosis of newly synthesized FN remain elusive. Here we show that, on Rab21-elicited internalization, FN-bound/active α5β1 is recycled to the EC surface. We identify a pathway, comprising the regulators of post-Golgi carrier formation PI4KB and AP-1A, the small GTPase Rab11B, the surface tyrosine phosphatase receptor PTPRF and its adaptor PPFIA1, which we propose acts as a funnel combining FN secretion and recycling of active α5β1 integrin from the trans-Golgi network (TGN) to the EC surface, thus allowing FN fibrillogenesis. In this framework, PPFIA1 interacts with active α5β1 integrin and localizes close to EC adhesions where post-Golgi carriers are targeted. We show that PPFIA1 is required for FN polymerization-dependent vascular morphogenesis, both in vitro and in the developing zebrafish embryo.
Highlights
Basolateral polymerization of cellular fibronectin (FN) into a meshwork drives endothelial cell (EC) polarity and vascular remodelling
PTPRF interacting protein a1 (PPFIA1) localized to the vicinity of centrally located vinculincontaining fibrillar adhesions (Fig. 1a, magnified panel 2), where active a5b1 integrins, as recognized by SNAKA51 monoclonal antibody[34,35], predominantly localized[14]
These findings were further substantiated by super-resolved timed-gated stimulated emission depletion (g-STED) confocal microscopy analyses of PPFIA1-GFP transfected and anti-vinculin-stained or anti-active a5b1 integrin-stained ECs (Fig. 1a,b, g-STED)
Summary
Basolateral polymerization of cellular fibronectin (FN) into a meshwork drives endothelial cell (EC) polarity and vascular remodelling. A complex machinery composed of the transmembrane glycoprotein neuropilin 1 (Nrp1), its cytosolic interactor GAIP interacting protein C terminus, member 1 (GIPC1) and the associated motor myosin VI (MYO6) selectively controls the endocytosis of FN fragments bound to active a5b1 integrins from the surface of ECs11,14. The importance of this process is highlighted by the severe impairment of FN fibrillogenesis that occurs in ECs on disruption of Nrp[1] signaling[14]. We identify PPFIA1 as a key component of the molecular machinery that in ECs physically binds and controls the recycling of endocytosed active a5b1 integrin to the cell surface and the basolaterally-polarized fibrillogenesis of newly synthesized FN
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