Progranulin, a glycoprotein deficient in frontotemporal dementia, is a novel substrate of several protein disulfide isomerase family proteins
Almeida, Sandra ; Zhou, Lijuan ; Gao, Fen-Biao
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UMass Chan Affiliations
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Keywords
Biological Markers
Cerebral Cortex
Endoplasmic Reticulum
Frontotemporal Dementia
Gene Expression Regulation
Glycoproteins
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins
Mice
Microglia
Molecular Chaperones
Neurons
Protein Binding
Protein Disulfide-Isomerases
Protein Transport
Life Sciences
Medicine and Health Sciences
Neurology
Neuroscience and Neurobiology
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Abstract
The reduced production or activity of the cysteine-rich glycoprotein progranulin is responsible for about 20% of cases of familial frontotemporal dementia. However, little is known about the molecular mechanisms that govern the level and secretion of progranulin. Here we show that progranulin is expressed in mouse cortical neurons and more prominently in mouse microglia in culture and is abundant in the endoplasmic reticulum (ER) and Golgi. Using chemical crosslinking, immunoprecipitation, and mass spectrometry, we found that progranulin is bound to a network of ER Ca(2+)-binding chaperones including BiP, calreticulin, GRP94, and four members of the protein disulfide isomerase (PDI) family. Loss of ERp57 inhibits progranulin secretion. Thus, progranulin is a novel substrate of several PDI family proteins and modulation of the ER chaperone network may be a therapeutic target for controlling progranulin secretion.
Source
Almeida S, Zhou L, Gao F-B (2011) Progranulin, a Glycoprotein Deficient in Frontotemporal Dementia, Is a Novel Substrate of Several Protein Disulfide Isomerase Family Proteins. PLoS ONE 6(10): e26454. doi:10.1371/journal.pone.0026454. Link to article on publisher's site