Prosaposin: a protein with differential sorting and multiple functions

Area of Science:

• Cell Biology
• Molecular Biology
• Neuroscience

Background:

• Protein trafficking in eukaryotes relies on the endoplasmic reticulum and Golgi apparatus for modification, sorting, and distribution.
• Lysosomal proteins are typically directed via mannose-6-phosphate receptors (MPR), but exceptions exist.
• I-cell disease revealed an MPR-independent pathway for lysosomal targeting.

Purpose of the Study:

• To elucidate the mechanism of lysosomal targeting for prosaposin, particularly in the context of MPR pathway disruptions.
• To identify the specific protein interactions and motifs responsible for prosaposin's lysosomal localization.
• To explore the broader functions and distribution of prosaposin beyond its lysosomal role.

Main Methods:

• Investigated prosaposin trafficking in relation to lysosomal sorting pathways.
• Utilized deletion and mutational analysis of prosaposin's C-terminus.
• Examined the interaction between prosaposin and its newly identified receptor, sortilin.
• Assessed the extracellular functions of prosaposin in nervous tissues.

Main Results:

• Discovery of sortilin as a novel lysosomal sorting receptor for prosaposin.
• Identified the C-terminus of prosaposin, specifically a motif in its first half, as crucial for sortilin binding and lysosomal transport.
• Demonstrated that prosaposin can be secreted extracellularly, influencing nervous system functions.
• Confirmed prosaposin's presence in various bodily fluids, suggesting diverse physiological roles.

Conclusions:

• Sortilin mediates lysosomal targeting of prosaposin through C-terminal interactions, independent of the MPR pathway.
• Prosaposin exhibits extracellular functions impacting nervous system signaling.
• Prosaposin is a multifunctional protein with roles beyond lysosomal homeostasis, essential for nervous system development and maintenance.