Review
Sorting of lysosomal proteins

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Abstract

Lysosomes are composed of soluble and transmembrane proteins that are targeted to lysosomes in a signal-dependent manner. The majority of soluble acid hydrolases are modified with mannose 6-phosphate (M6P) residues, allowing their recognition by M6P receptors in the Golgi complex and ensuing transport to the endosomal/lysosomal system. Other soluble enzymes and non-enzymatic proteins are transported to lysosomes in an M6P-independent manner mediated by alternative receptors such as the lysosomal integral membrane protein LIMP-2 or sortilin. Sorting of cargo receptors and lysosomal transmembrane proteins requires sorting signals present in their cytosolic domains. These signals include dileucine-based motifs, DXXLL or [DE]XXXL[LI], and tyrosine-based motifs, YXXØ, which interact with components of clathrin coats such as GGAs or adaptor protein complexes. In addition, phosphorylation and lipid modifications regulate signal recognition and trafficking of lysosomal membrane proteins. The complex interaction of both luminal and cytosolic signals with recognition proteins guarantees the specific and directed transport of proteins to lysosomes.

Abbreviations

ER
endoplasmic reticulum
M6P
mannose 6-phosphate
TGN
trans-Golgi network
FGE
formylglycine-generating enzyme
UCE
uncovering enzyme
MPR46/CD-MPR
46 kDa cation-dependent mannose 6-phosphate receptor
MPR300/CI-MPR
300 kDa cation-dependent mannose 6-phosphate receptor
GGA
Golgi localized γ-ear containing ARF-binding protein
AP
adaptor protein
CK2
casein kinase 2
CCV
clathrin-coated vesicles
TCs
transport carriers
LAMP
lysosomal associated membrane protein

Keywords

Lysosomal protein
Posttranslational modification
GIcNac-1-phosphotransferase
Mannose 6-phosphate
Adaptor protein complex

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