Exposure at the cell surface is required for Gas3/PMP22 to regulate both cell death and cell spreading: Implication for the Charcot-Marie-Tooth type 1A and Dejerine-Sottas diseases

Gas3/PMP22 is a tetraspan membrane protein highly expressed in myelinating Schwann cells. Point mutations in the gas3/PMP22 gene account for the domin ant inherited peripheral neuropathies Charcot-Marie-Tooth type 1A disease ( CMT1A) and Dejerine-Sottas syndrome (DSS). Gas3/PMP22 can regulate apoptosi s and cell spreading in cultured cells. Gas3/PMP22 point mutations, which a re responsible for these diseases, are defective in this respect. In this r eport, we demonstrate that Gas3/PMP22-WT is exposed at the cell surface, wh ile its point-mutated derivatives are intracellularly retained, colocalizin g mainly with the endoplasmic reticulum (ER). The putative retrieval motif present in the carboxyl terminus of Gas3/PMP22 is not sufficient for the in tracellular sequestration of its point-mutated forms. On the contrary, the introduction of a retrieval signal at the carboxyl terminus of Gas3/PMP22-W T leads to its intracellular accumulation, which is accompanied by a failur e to trigger cell death as well as by changes in cell spreading. In additio n, by substituting the Asn at position 41 required for N-glycosylation, we provide evidence that N-glycosylation is required for the full effect on ce ll spreading, but it is not necessary for triggering cell death. Ln conclus ion, we suggest that the DSS and the CMT1A neuropathies derived from Feint mutations of Gas3/PMP22 might arise, at the molecular level, from a reduced exposure of Gas3/PMP22 at the cell surface, which is required to exert its biological functions.