Affiliation:
1. Departments of Cell Biology and Neuroscience, Program in Cellular Neuroscience, Neurodegeneration and Repair, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT
Abstract
Progranulin is a lysosomal protein whose haploinsufficiency causes frontotemporal dementia, while homozygous loss of progranulin causes neuronal ceroid lipofuscinosis, a lysosomal storage disease. The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interactions with prosaposin, another lysosomal protein, first occur within the lumen of the endoplasmic reticulum (ER) and are required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII-coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates that a network of interactions occurring early in the secretory pathway promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.
Funder
Bluefield Project to Cure FTD
Parkinson’s Disease Foundation
National Institutes of Health
Publisher
Rockefeller University Press
Cited by
11 articles.
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