Lysosomal Targeting of Cystinosin Requires AP ‐3

Cystinosin, a seven transmembrane ( TM ) lysosomal cystine transporter defective in the autosomal recessive lysosomal storage disorder, has been shown to be targeted to lysosomes via two sorting signals: a tyrosine‐based motif in its C‐terminal ( GYDQL ) and a non‐classical motif in its fifth inter‐ TM loop. Here, we show that the tyrosine‐based motif specifically interacts with AP ‐3 complex and functions as a ‘strong’ AP ‐3 motif responsible for direct intracellular targeting of cystinosin and the CD63 ‐cystinosin chimera ( CD63‐GYDQL ) to late endosomes/lysosomes.