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NRH2 is a trafficking switch to regulate sortilin localization and permit proneurotrophin‐induced cell death
Author(s) -
Kim Taeho,
Hempstead Barbara L
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.118
Subject(s) - biology , microbiology and biotechnology , programmed cell death , intracellular , cytoplasm , receptor , hek 293 cells , cell , cell membrane , gene silencing , cell surface receptor , apoptosis , biochemistry , gene
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.