[HTML][HTML] The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin

S Lefrancois, J Zeng, AJ Hassan, M Canuel… - The EMBO …, 2003 - embopress.org
S Lefrancois, J Zeng, AJ Hassan, M Canuel, CR Morales
The EMBO journal, 2003embopress.org
Most soluble lysosomal proteins bind the mannose 6‐phosphate receptor (M6P‐R) to be
sorted to the lysosomes. However, the lysosomes of I‐cell disease (ICD) patients, a
condition resulting from a mutation in the phosphotransferase that adds mannose 6‐
phosphate to hydrolases, have near normal levels of several lysosomal proteins, including
the sphingolipid activator proteins (SAPs), G M2 AP and prosaposin. We tested the
hypothesis that SAPs are targeted to the lysosomal compartment via the sortilin receptor. To …
Most soluble lysosomal proteins bind the mannose 6‐phosphate receptor (M6P‐R) to be sorted to the lysosomes. However, the lysosomes of I‐cell disease (ICD) patients, a condition resulting from a mutation in the phosphotransferase that adds mannose 6‐phosphate to hydrolases, have near normal levels of several lysosomal proteins, including the sphingolipid activator proteins (SAPs), G M2 AP and prosaposin. We tested the hypothesis that SAPs are targeted to the lysosomal compartment via the sortilin receptor. To test this hypothesis, a dominant‐negative construct of sortilin and a sortilin small interfering RNA (siRNA) were introduced into COS‐7 cells. Our results showed that both the truncated sortilin and the sortilin siRNA block the traffic of G M2 AP and prosaposin to the lysosomal compartment. This observation was confirmed by a co‐immunoprecipitation, which demonstrated that G M2 AP and prosaposin are interactive partners of sortilin. Furthermore, a dominant‐negative mutant GGA prevented the trafficking of prosaposin and G M2 AP to lysosomes. In conclusion, our results show that the trafficking of SAPs is dependent on sortilin, demonstrating a novel lysosomal trafficking.
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