The prion protein inhibits monocytic cell migration by stimulating β1 integrin adhesion and uropod formation

Abstract

The broad tissue distribution and evolutionary conservation of the glycosylphosphatidylinositol (GPI)-anchored prion protein (PrP, also known as PRNP) suggests that it plays a role in cellular homeostasis. Given that integrin adhesion determines cell behavior, the proposed role of PrP in cell adhesion might underlie the various in vitro and in vivo effects associated with PrP loss-of-function, including the immune phenotypes described in PrP −/− mice. Here, we investigated the role of PrP in the adhesion and (transendothelial) migration of human ( pro)monocytes. We found that PrP regulates β1-integrinmediated adhesion of monocytes. Additionally, PrP controls the cell morphology and migratory behavior of monocytes: PrP-silenced cells show deficient uropod formation on immobilized VCAM and display bleb-like protrusions on the endothelium. Our data further show that PrP regulates ligand-induced integrin activation. Finally, we found that PrP controls the activation of several proteins involved in cell adhesion and migration, including RhoA and its effector cofilin, as well as proteins of the ERM family. We propose that PrP modulates β1 integrin adhesion and migration of monocytes through RhoA-induced actin remodeling mediated by cofilin, and through the regulation of ERM-mediated membrane-cytoskeleton linkage.

Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells

“…Interestingly, it was demonstrated that PrP C -null mice present increased paracellular permeability, with lower levels of E-cadherin, desmoplakin, occluding, and other proteins related to cell-cell junctions in intestinal tissues [45]. Furthermore, it was reported that PrP C is able to regulate β1 integrin adhesiveness modulating ligand-induced changes in integrin activation [46]; however, its depletion had no effect on total β1 integrin expression levels [47]. These data suggest that PrP C may be capable of recruiting cell adhesion molecules to the cell surface of GSCs, raising the hypothesis of PrP C modulating invasion-related processes.…”

Leukocyte adhesion and polarization: Role of glycosylphosphatidylinositol-anchored proteins

“… 19,28 Similarly, PrP was found to colocalize with β1 integrins on membrane caps in polarized monocytic cells and to regulate β1 integrin-mediated monocyte adhesion to fibronectin and VCAM-1. 20 PrP-deficient monocytes display a reduced ability to bind polyvalent VCAM-1, without significant alterations in β1 integrin affinity, suggesting that PrP silencing reduces the valency of integrin adhesion. In agreement with the fact that increases in integrin valency are important to resist blood flow shear stress forces, PrP-deficient monocytes displayed reduced firm adhesion to the endothelium under shear flow conditions.…”

“…Migrating human monocytic U937 leukocytes plated on immobilized VCAM-1 and CXCL12 acquire a polarized shape consisting of a leading edge followed by the cell body and a rear end formed by the uropod, where b1 integrins and phosphorylated ERM proteins accumulate. 20 …”

The Good, the Bad, and the Ugly of Dendritic Cells during Prion Disease

“…A separate study has proposed that PrP C may regulate human monocyte migration by modulating cell adhesion dynamics [ 52 ]. The authors propose that PrP C regulates β 1-integrin-mediated adhesion by modulating the remodelling of the actin cytoskeleton through the RhoA-cofilin pathway.…”

“…This implies that DC could be manipulated to provide immunotherapeutic protection against prion diseases [ 54 , 106 , 107 ]. (6) The physiological function of cellular PrP C is uncertain but in DC may play a role in the immune synapse or in the regulation of cell migration [ 51 , 52 ].…”