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Progranulin-derived granulin E and lysosome membrane protein CD68 interact to reciprocally regulate their protein

Mariela Nunez Santos1, Daniel H Paushter1, Tingting Zhang1

  • 1Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA.

The Journal of Biological Chemistry
|August 6, 2022
PubMed

Insights

Progranulin (PGRN) and CD68, a lysosome protein, interact to regulate each other. CD68 deficiency reduces granulin E levels, while PGRN deficiency alters CD68 molecular weight, revealing a novel protein homeostasis mechanism.

Area of Science:

  • Neurobiology
  • Cell Biology
  • Molecular Medicine

Background:

  • Progranulin (PGRN) is a glycoprotein linked to neurodegenerative diseases, expressed in microglia and macrophages.
  • PGRN is processed into granulin peptides within lysosomes, but their functions remain largely unknown.
  • CD68 is a lysosome membrane protein found in hematopoietic cells.

Purpose of the Study:

  • To investigate the functional relationship between progranulin (PGRN) and the lysosome membrane protein CD68.
  • To identify the specific granulin peptides interacting with CD68.
  • To elucidate the reciprocal regulation between PGRN and CD68.

Main Methods:

  • Co-immunoprecipitation and deletion analysis to identify CD68 binding domains.
  • Western blotting to assess protein levels and molecular weight changes in PGRN and CD68 deficient cells.
  • Cellular localization studies using immunofluorescence.

Main Results:

  • CD68 binds to both PGRN and the specific granulin peptide, granulin E, via its mucin-proline-rich domain.
  • CD68 deficiency specifically decreases granulin E levels without affecting other granulin peptides or PGRN localization.
  • PGRN deficiency alters CD68's molecular weight but not its cellular localization.

Conclusions:

  • Granulin E and CD68 reciprocally regulate each other's protein homeostasis.
  • This interaction highlights a novel mechanism for lysosomal protein regulation.
  • Findings provide insights into PGRN's role in cellular processes beyond neurodegeneration.
Keywords:
CD68frontotemporal dementiagranulinlysosomemicrogliaprogranulin

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