2. Academic Validation
  3. Progranulin-derived granulin E and lysosome membrane protein CD68 interact to reciprocally regulate their protein homeostasis

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

  • J Biol Chem. 2022 Sep;298(9):102348. doi: 10.1016/j.jbc.2022.102348.
Mariela Nunez Santos 1,  Daniel H Paushter 1,  Tingting Zhang 1,  Xiaochun Wu 1,  Tuancheng Feng 1,  Jiaoying Lou 2,  Huan Du 1,  Stephanie M Becker 1,  Robert Fragoza 3,  Haiyuan Yu 3,  Fenghua Hu 4
Affiliations

Affiliations

  • 1 Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA.
  • 2 Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA; Department of Gynecology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China.
  • 3 Department of Computational Biology, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA.
  • 4 Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA. Electronic address: [email protected].
PMID: 35933009 DOI: 10.1016/j.jbc.2022.102348
Abstract

Progranulin (PGRN) is a glycoprotein implicated in several neurodegenerative diseases. It is highly expressed in microglia and macrophages and can be secreted or delivered to the lysosome compartment. PGRN comprises 7.5 granulin repeats and is processed into individual granulin Peptides within the lysosome, but the functions of these Peptides are largely unknown. Here, we identify CD68, a lysosome membrane protein mainly expressed in hematopoietic cells, as a binding partner of PGRN and PGRN-derived granulin E. Deletion analysis of CD68 showed that this interaction is mediated by the mucin-proline-rich domain of CD68. While CD68 deficiency does not affect the lysosomal localization of PGRN, it results in a specific decrease in the levels of granulin E but no other granulin Peptides. On the other hand, the deficiency of PGRN, and its derivative granulin Peptides, leads to a significant shift in the molecular weight of CD68, without altering CD68 localization within the cell. Our results support that granulin E and CD68 reciprocally regulate each other's protein homeostasis.

Keywords

CD68; frontotemporal dementia; granulin; lysosome; microglia; progranulin.

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