Modulation of signal transduction through the cellular prion protein is linked to its incorporation in lipid rafts

Abstract

Because expressed at a significant level at the membrane of human T cells, we made the hypothesis that the cellular prion protein (PrPc) could behave as a receptor, and be responsible for signal transduction. PrPc engagement by specific antibodies was observed to induce an increase in cytosolic calcium concentration and led to enhanced activity of Src protein tyrosine kinases. Antibodies to CD4 and CD59 did not influence calcium fluxes or signaling. The effect was maximal after the formation of a network involving avidin and biotinylated antibody to PrPc and was inhibited after raft disruption. PrPc localization was not restricted to rafts in resting cells but engagement was a prerequisite for signaling induction, with concomitant PrPc recruitment into rafts. These results suggest a role for PrPc in signaling pathways, and show that lateral redistribution of the protein into rafts is important for subsequent signal transduction.

Functional Implication of Cellular Prion Protein in Antigen-Driven Interactions between T Cells and Dendritic Cells

“…First, we have considered simultaneously the two cell types of the immunological synapse, T cells and DC, whereas most studies published so far have focused on the T cell partner only (29 -37). Second, at variance with other studies examining polyclonal T cell activation by mitogenic lectins (29,30), Ab cross-linking (35)(36)(37), or hypothermic shock (38), we have looked at more physiological conditions. Even if allogeneic stimulation or MHC-peptide activation of TCR transgenic T cells mimic only the normal development of an immune response, the two models imply the formation of T/DC synapses, specific recognition of antigenic patterns, and physiological signal transduction pathways.…”

“…The protein appears to be tightly regulated on certain lymphoreticular subsets such as T cell, monocytes, and medullary precursors (26 -28), and anti-PrPC Abs cause partial inhibition of mitogen-driven T cell proliferation (29 -32). More recent data based on confocal imaging and immunoprecipitation have documented, shortly after T cell polyclonal activation, a shift of GPI-anchored PrPC within lipidic rafts, in physical association with a cohort of molecules with signaling functions such as Src, fyn, lck, Zap70, linker for activation of T cells (LAT), NADPH, and MAPKs (33)(34)(35)(36)(37)(38).…”

Trafficking of PrPcto mitochondrial raft-like microdomains during cell apoptosis

“…Crosslink of PrP C on the surface of T-cell lines has been associated with various cellular responses, such as intracellular calcium mobilization, Src and Erk kinase activation or capping of lipid microdomains 11 in a large membrane zone where PrP C colocalize with Thy-1 or fyn kinase. 12 The contribution of PrP C to the classical T-lymphocyte activation process has been characterized by clustering the T-cell receptor component CD3, as well as PrP C , with soluble and surface immobilized antibodies, respectively.…”

Physiological role of the cellular prion protein

“…Due to its membrane localization, this subterfuge has been used with the aim to demonstrate a potential role of PrP C as a membrane receptor. Crosslink of PrP C on the surface of T cell lines has been associated with various cellular responses like intracellular calcium mobilization, Src and Erk kinase activation or capping of lipidic microdomains in a large membrane zone where PrP C colocalize with Thy-1 or fyn kinase [44,100]. The contribution of PrP C to the classical T-lymphocyte activation process has been characterized by clustering the T-cell receptor component CD3ε as well as PrP with soluble and surfaceimmobilized antibodies, respectively.…”