NRH2 is a trafficking switch to regulate sortilin localization and permit proneurotrophin-induced cell death.

Proneurotrophins mediate neuronal apoptosis using a dual receptor complex of sortilin and p75(NTR). Although p75(NTR) is highly expressed on the plasma membrane and accessible to proneurotrophin ligands, sortilin is primarily localized to intracellular membranes, limiting the formation of a cell surface co-receptor complex. Here, we show that the mammalian p75(NTR) homologue NRH2 critically regulates the expression of sortilin on the neuronal cell surface and promotes p75(NTR) and sortilin receptor complex formation, rendering cells responsive to proneurotrophins. This is accomplished by interactions between the cytoplasmic domains of NRH2 and sortilin that impair lysosomal degradation of sortilin. In proneurotrophin-responsive neurons, acute silencing of endogenous NRH2 significantly reduces cell surface-expressed sortilin and abolishes proneurotrophin-induced neuronal death. Thus, these data suggest that NRH2 acts as a trafficking switch to impair lysosomal-dependant sortilin degradation and to redistribute sortilin to the cell surface, rendering p75(NTR)-expressing cells susceptible to proneurotrophin-induced death.