{"doi":"10.1016/j.jbc.2022.102348","title":"Progranulin-derived granulin E and lysosome membrane protein CD68 interact to reciprocally regulate their protein homeostasis","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. 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. Frontotemporal lobar degeneration is a progressive neurodegenerative disease characterized by changes in personality and behavior as well as cognitive decline and language impairments (https://www.uptodate.com/contents/frontotemporal-dementia-epidemiology-pathology-and-pathogenesis) (1Neary D. Snowden J.S. Gustafson L. Passant U. Stuss D. Black S. et al.Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.Neurology. 1998; 51: 1546-1554Crossref PubMed Scopus (4546) Google Scholar, 2Rabinovici G.D. Miller Bruce L. Frontotemporal lobar degeneration.CNS Drugs. 2010; 24: 375-398Crossref PubMed Scopus (303) Google Scholar). Mutation in the granulin (GRN) gene, resulting in haploinsufficiency of the progranulin (PGRN) protein, is one of the leading causes of frontotemporal lobar degeneration (3Baker M. Mackenzie I.R. Pickering-Brown S.M. Gass J. Rademakers R. Lindholm C. et al.Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.Nature. 2006; 442: 916-919Crossref PubMed Scopus (1663) Google Scholar, 4Cruts M. Gijselinck I. van der Zee J. Engelborghs S. Wils H. Pirici D. et al.Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.Nature. 2006; 442: 920-924Crossref PubMed Scopus (1279) Google Scholar, 5Gass J. Cannon A. Mackenzie I.R. Boeve B. Baker M. Adamson J. et al.Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.Hum. Mol. Genet. 2006; 15: 2988-3001Crossref PubMed Scopus (494) Google Scholar), with over 70 disease-associated GRN mutations identified (https://www.uptodate.com/contents/frontotemporal-dementia-epidemiology-pathology-and-pathogenesis). PGRN is a secreted glycoprotein that is involved in many cellular processes, includ","journal":"Journal of Biological Chemistry","year":2022,"id":264355,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9649,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":922407,"name":"Daniel H. Paushter","orcid":null,"position":1,"is_corresponding":false},{"id":861834,"name":"Tingting Zhang","orcid":"0000-0002-7868-9624","position":2,"is_corresponding":false},{"id":921964,"name":"Xiaochun Wu","orcid":"0000-0002-2054-5329","position":3,"is_corresponding":false},{"id":473857,"name":"Tuancheng Feng","orcid":"0000-0002-4833-2659","position":4,"is_corresponding":false},{"id":922408,"name":"Jiaoying Lou","orcid":null,"position":5,"is_corresponding":false},{"id":921965,"name":"Huan Du","orcid":"0000-0003-0728-7844","position":6,"is_corresponding":false},{"id":921966,"name":"Stephanie M. Becker","orcid":"0000-0003-0565-5930","position":7,"is_corresponding":false},{"id":268020,"name":"Robert Fragoza","orcid":"0000-0002-9892-4169","position":8,"is_corresponding":false},{"id":268021,"name":"Haiyuan Yu","orcid":"0000-0001-7597-6049","position":9,"is_corresponding":false},{"id":473858,"name":"Fenghua Hu","orcid":"0000-0002-6447-9992","position":10,"is_corresponding":false},{"id":922406,"name":"Mariela Nunez Santos","orcid":null,"position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T00:26:37.567338Z","pmid":"35933009","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}