Progranulin takes an alternate route to lysosomes

Zhou et al. reveal that the disease-related protein progranulin gets a “piggyback” ride to lysosomes by binding to another lysosomal protein, prosaposin.

Mutations in the gene encoding progranulin cause the neurodegenerative diseases frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Although progranulin can be secreted from cells to act as a neurotrophic factor, the protein is also required inside cells to maintain the function of lysosomes. Progranulin is targeted to these organelles by the sorting receptor sortilin but is only partially mislocalized in sortilin-deficient neurons, suggesting that it can also reach lysosomes via a different route.

Zhou et al. found that progranulin binds to prosaponin, another protein that can either be secreted or delivered to lysosomes. Progranulin’s localization to lysosomes was partially reduced in neurons lacking prosaposin, and completely abolished in prosaposin-deficient fibroblasts, a cell type that expresses hardly any sortilin. Ectopically expressing sortilin, however, restored progranulin’s localization to fibroblast lysosomes, indicating that the sortilin and prosaposin trafficking pathways operate independently of each other.

Prosaposin promoted the delivery of both secreted and newly synthesized progranulin to lysosomes, in part by linking the protein to the cation-independent mannose 6-phosphate receptor. Another sorting receptor, LRP1, was also required for the prosaposin-dependent retrieval of secreted progranulin.

It remains to be seen exactly what progranulin does once it is delivered to lysosomes. Senior author Fenghua Hu is also interested in whether prosaposin and progranulin influence each other’s function, both inside and outside the cell.