{"doi":"10.1194/jlr.ra120000964","title":"Insights into the kinetics and dynamics of the furin-cleaved form of PCSK9","abstract":"Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism by inducing the degradation of hepatic low density lipoprotein receptors (LDLRs). Plasma PCSK9 has 2 main molecular forms: a 62 kDa mature form (PCSK9_62) and a 55 kDa, furin-cleaved form (PCSK9_55). PCSK9_55 is considered less active than PCSK9_62 in degrading LDLRs. We aimed to identify the site of PCSK9_55 formation (intracellular vs. extracellular) and to further characterize the LDLR-degradative function of PCSK9_55 relative to PCSK9_62. Coexpressing PCSK9_62 with furin in cell culture induced formation of PCSK9_55, most of which was found in the extracellular space. Under the same conditions, we found that i) adding a cell-permeable furin inhibitor preferentially decreased the formation of PCSK9_55 extracellularly; ii) using pulse-chase analysis, we observed the formation of PCSK9_55 exclusively extracellularly in a time-dependent manner. A recombinant form of PCSK9_55 was efficiently produced but displayed impaired secretion that resulted in its intracellular trapping. However, the nonsecreted PCSK9_55 was able to induce degradation of LDLR, though with 50% lower efficiency than PCSK9_62. Collectively, our data show that 1) PCSK9_55 is formed extracellularly; 2) PCSK9_55 has a shorter half-life; 3) there is a small intracellular pool of PCSK9_55 that is not secreted; and 4) PCSK9_55 retained within the cell maintains a reduced efficiency to cause LDLR degradation.","journal":"Journal of Lipid Research","year":2020,"id":69426,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":367587,"name":"Joshua Hay","orcid":"0009-0000-7377-1269","position":1,"is_corresponding":false},{"id":368279,"name":"Emma Gurcan","orcid":null,"position":2,"is_corresponding":false},{"id":141412,"name":"Larry L. David","orcid":null,"position":3,"is_corresponding":false},{"id":341552,"name":"Paul Müeller","orcid":"0000-0001-9315-0152","position":4,"is_corresponding":false},{"id":341551,"name":"Hagai Tavori","orcid":"0000-0001-7553-9543","position":5,"is_corresponding":false},{"id":159550,"name":"Michael D Shapiro","orcid":"0000-0002-9071-3287","position":6,"is_corresponding":false},{"id":367588,"name":"Nathalie Pamir","orcid":"0000-0002-2074-888X","position":7,"is_corresponding":false},{"id":367589,"name":"Sergio Fazio","orcid":"0000-0002-8145-8034","position":8,"is_corresponding":false},{"id":292253,"name":"Carlota Oleaga","orcid":"0000-0002-2146-9671","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T21:42:22.705573Z","pmid":"33429337","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":[]}