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The trafficking of prosaposin (SGP‐1) and GM 2 AP to the lysosomes of TM4 sertoli cells is mediated by sortilin and monomeric adaptor proteins
Author(s) -
Hassan A. Jacob,
Zeng Jibin,
Ni Xiaoyan,
Morales Carlos R.
Publication year - 2004
Publication title -
molecular reproduction and development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 105
eISSN - 1098-2795
pISSN - 1040-452X
DOI - 10.1002/mrd.20096
Subject(s) - biology , signal transducing adaptor protein , sertoli cell , microbiology and biotechnology , spermatogenesis , signal transduction , endocrinology
Prosaposin (SGP‐1) and GM 2 activator protein (GM 2 AP) are soluble sphingolipid activator proteins (SAPs) that are targeted to the lysosomal compartment of Sertoli cells to aid hydrolases in the breakdown of glycosphingolipids. To reach the lysosome, most soluble proteins must interact with the mannose 6‐phosphate receptor (MPR). To be sorted from the Golgi, the MPR must bind to the Golgi associated, γ‐adaptin homologous, ARF binding proteins (GGAs), a group of monomeric adaptor proteins responsible for the recruitment of clathrin. It is well established, however, that the lysosomes of I‐cell disease (ICD) patients have near normal levels of several lysosomal proteins, including prosaposin and GM 2 AP. ICD results from a mutation in the phosphotransferase that adds mannose 6‐phosphate to hydrolases. Thus, prosaposin and GM 2 AP can traffic to lysosomes in a MPR independent manner. Previous work has demonstrated that an interaction with sphingomyelin in the Golgi membrane is necessary for the targeting of prosaposin by an unknown receptor. Using a TM4 Sertoli cell line, we tested the hypothesis that prosaposin and GM 2 AP are targeted to the lysosomal compartment via the sortilin receptor, which has been recently shown to have a GGA binding motif. Interestingly, dominant‐negative GGAs, unable to bind clathrin to shuttle from the Golgi, prevented the trafficking of prosaposin and GM 2 AP to lysosomes. A dominant negative construct of sortilin lacking the GGA binding domain retained prosaposin and GM 2 AP in the Golgi. In conclusion, our results showed that the trafficking of prosaposin and GM 2 AP to the lysosome is dependent on sortilin. Mol. Reprod. Dev. 68: 476–483, 2004. © 2004 Wiley‐Liss, Inc.