Progranulin, a glycoprotein deficient in frontotemporal dementia, is a novel substrate of several protein disulfide isomerase family proteins

PLoS One. 2011;6(10):e26454. doi: 10.1371/journal.pone.0026454. Epub 2011 Oct 18.


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.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cerebral Cortex / cytology
  • Endoplasmic Reticulum / metabolism
  • Frontotemporal Dementia / metabolism*
  • Gene Expression Regulation
  • Glycoproteins / deficiency*
  • Glycoproteins / metabolism*
  • Granulins
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / deficiency*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Microglia / metabolism
  • Molecular Chaperones / metabolism
  • Neurons / metabolism
  • Progranulins
  • Protein Binding
  • Protein Disulfide-Isomerases / metabolism*
  • Protein Transport


  • Biomarkers
  • Glycoproteins
  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Progranulins
  • PDIA6 protein, human
  • Protein Disulfide-Isomerases
  • PDIA3 protein, human