title: Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin.
abstract: Mutations in the progranulin (PGRN) gene have been linked to two distinct neurodegenerative diseases, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests a critical role of PGRN in lysosomes. However, how PGRN is trafficked to lysosomes is still not clear. Here we report a novel pathway for lysosomal delivery of PGRN. We found that prosaposin (PSAP) interacts with PGRN and facilitates its lysosomal targeting in both biosynthetic and endocytic pathways via the cation-independent mannose 6-phosphate receptor and low density lipoprotein receptor-related protein 1. PSAP deficiency in mice leads to severe PGRN trafficking defects and a drastic increase in serum PGRN levels. We further showed that this PSAP pathway is independent of, but complementary to, the previously identified PGRN lysosomal trafficking mediated by sortilin. Collectively, our results provide new understanding on PGRN trafficking and shed light on the molecular mechanisms behind FTLD and NCL caused by PGRN mutations.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853 Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
authors.forename: Xiaolai
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853 Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853 Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853 Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
authors.forename: Francisco
authors.initials: F
authors.lastname: Bastos de Oliveira
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
authors.forename: William J
authors.initials: WJ
authors.lastname: Brown
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853 Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
authors.forename: Marcus B
authors.initials: MB
authors.lastname: Smolka
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853 Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853 fh87@cornell.edu.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Hu
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004705:Endocytosis; D005838:Genotype; D000077155:Granulins; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D000077153:Progranulins; D011485:Protein Binding; D021381:Protein Transport; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D049231:Saposins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000077153:Progranulins; D017527:Receptor, IGF Type 2; D011973:Receptors, LDL; D049231:Saposins; D025521:Tumor Suppressor Proteins; D000099183:Sortilin; C492314:GRN protein, human; C120204:Grn protein, mouse; C486645:Lrp1 protein, mouse; C483345:PSAP protein, human; C483344:Psap protein, mouse; C034304:cation-dependent mannose-6-phosphate receptor