Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin

Xiaolai Zhou; Lirong Sun; Francisco Bastos de Oliveira; Xiaoyang Qi; William J Brown; Marcus B Smolka; Ying Sun; Fenghua Hu

doi:10.1083/jcb.201502029

Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin

J Cell Biol. 2015 Sep 14;210(6):991-1002. doi: 10.1083/jcb.201502029.

Authors

Xiaolai Zhou¹, Lirong Sun², Francisco Bastos de Oliveira¹, Xiaoyang Qi³, William J Brown⁴, Marcus B Smolka¹, Ying Sun⁵, Fenghua Hu⁶

Affiliations

¹ Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853 Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
² 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.
³ Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
⁴ Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
⁵ Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
⁶ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Vesicular Transport / deficiency
Adaptor Proteins, Vesicular Transport / genetics
Adaptor Proteins, Vesicular Transport / metabolism*
Animals
Endocytosis
Genotype
Granulins
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins / deficiency
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Low Density Lipoprotein Receptor-Related Protein-1
Lysosomes / metabolism*
Lysosomes / pathology
Mice, Inbred C57BL
Mice, Knockout
Nerve Degeneration
Neurons / metabolism*
Neurons / pathology
Phenotype
Progranulins
Protein Binding
Protein Transport
Receptor, IGF Type 2 / metabolism
Receptors, LDL / metabolism
Saposins / deficiency
Saposins / genetics
Saposins / metabolism*
Transfection
Tumor Suppressor Proteins / metabolism

Substances

Adaptor Proteins, Vesicular Transport
GRN protein, human
Granulins
Grn protein, mouse
Intercellular Signaling Peptides and Proteins
Low Density Lipoprotein Receptor-Related Protein-1
Lrp1 protein, mouse
PSAP protein, human
Progranulins
Psap protein, mouse
Receptor, IGF Type 2
Receptors, LDL
Saposins
Tumor Suppressor Proteins
cation-dependent mannose-6-phosphate receptor
sortilin

Abstract

Publication types

MeSH terms

Substances

Grants and funding