{"gene":"PCSK7","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1996,"finding":"PCSK7 (PC7) encodes a type I membrane-bound glycoprotein with a 36-aa signal peptide, 104-aa prosegment ending in RAKR, and a 747-aa mature serine proteinase; phylogenetic analysis places it as the most divergent mammalian convertase and closest to yeast kexin/krp convertases.","method":"cDNA cloning, sequence analysis, Northern blot, in situ hybridization, chromosomal linkage mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — foundational biochemical characterization with multiple orthogonal methods (cDNA sequencing, phylogenetics, Northern blot, chromosomal mapping), replicated across subsequent studies","pmids":["8622945"],"is_preprint":false},{"year":1997,"finding":"Rat PC7 is synthesized as a 101-kDa glycosylated zymogen, processed to an 89-kDa mature form in the endoplasmic reticulum; enzymatic assays show pH optimum, Ca2+ dependence, and cleavage specificity largely similar to furin but with some kexin-like substrate preferences; PC7 correctly processes peptides containing the pro-PTH and pro-PC4 processing sites but not a pro-EGF site.","method":"Vaccinia-virus recombinant overexpression in BSC40 cells, fluorogenic peptide substrate assays, synthetic peptide cleavage, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic characterization with multiple substrates and mutants, foundational biochemistry paper","pmids":["9242622"],"is_preprint":false},{"year":1997,"finding":"PC7 cleaves HIV-1 gp160 into gp120/gp41 in a cell-type-specific manner (active in BSC40 and T4 lymphocyte contexts) and in vitro on a synthetic peptide spanning the cleavage site; both furin and PC7 are upregulated 5–10-fold in HIV-replication-promoting activated T4 lymphocytes.","method":"Co-expression in BSC40 and AtT20 cells, in vitro gp160 cleavage assay, RT-PCR","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based co-expression plus in vitro assay, single lab, two orthogonal methods","pmids":["9094426"],"is_preprint":false},{"year":1999,"finding":"Purified recombinant prosegments of furin and PC7 are potent, moderately selective inhibitors of their parent enzymes in vitro (inhibiting fluorogenic peptide cleavage and HIV gp160 processing); short C-terminal decapeptides of the prosegments retain inhibitory activity with the P1 Arg being essential; expressed ex vivo via vaccinia virus, the prosegments inhibit processing of NGF and BDNF in trans.","method":"In vitro fluorogenic peptide assay, recombinant prosegment purification, vaccinia virus ex vivo expression, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro inhibition with mutagenesis (P1 Arg requirement) and ex vivo validation, multiple orthogonal methods","pmids":["10567353"],"is_preprint":false},{"year":1999,"finding":"PC7 overexpression increases APPα secretion and reduces Aβ40/42 levels in HEK293 cells; this effect is blocked by α1-PDX (a proprotein convertase inhibitor), indicating PC7 participates in the constitutive α-secretase pathway for APP processing.","method":"Transient transfection in HEK293 cells, ELISA/immunoassay for APPα and Aβ40/42, α1-PDX inhibitor","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression and pharmacological inhibition in human cells, single lab, two complementary approaches","pmids":["10537065"],"is_preprint":false},{"year":1999,"finding":"Furin and PC7 mRNAs and proteins co-localize with NGF in Schwann cells, macrophages, and perivascular smooth muscle cells of injured sciatic nerve, and both convertases are upregulated after nerve lesion, suggesting a role in pro-NGF processing.","method":"Northern blot, immunocytochemistry, in situ hybridization on nerve explants and in vivo injury model","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization and co-regulation data without direct processing assay, replicated in vivo and ex vivo","pmids":["9888313"],"is_preprint":false},{"year":2000,"finding":"PC7 does not process integrin α-subunit precursors (pro-α5, α6, αv) either in vitro or ex vivo in LoVo cells, despite similar cleavage-site sequences to known PC7 substrates, indicating that substrate conformation determines PC7 accessibility.","method":"In vitro cleavage assay with recombinant PC7, LoVo cell co-expression (ex vivo), Western blot","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro and ex vivo assays, negative result explicitly established with both methods, single lab","pmids":["10657249"],"is_preprint":false},{"year":2000,"finding":"A 24-residue C-terminal peptide of the PC7 prosegment (residues 81p–104p) inhibits PC7 with Ki = 7 nM and adopts a helical conformation in solution; the folded structure is proposed to underlie its potency as a competitive inhibitor.","method":"Enzyme inhibition assay, NMR structure determination with NOE restraints","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure by NMR plus functional Ki measurement in the same study, single lab but two orthogonal methods","pmids":["10715106"],"is_preprint":false},{"year":2003,"finding":"Furin, PC5, and PC7 cleave proVEGF-C within the dibasic motif HSIIRR227↓SL to generate mature VEGF-C; this processing is required for VEGF-C-induced angiogenesis, lymphangiogenesis, and tumor growth in nude mice.","method":"Co-transfection in furin-deficient LoVo cells, in vitro fluorogenic peptide digestion, subcutaneous CHO cell injection into nude mice, cleavage-site mutagenesis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — cell-based processing assay, in vitro biochemical assay, site-directed mutagenesis, and in vivo tumorigenesis model, multiple orthogonal methods","pmids":["12782675"],"is_preprint":false},{"year":2008,"finding":"PC7 (along with Furin, PACE4, and PC5) cleaves the preprohepcidin convertase site RRRRR59↓DT to generate active hepcidin; cleavage was demonstrated in Huh-7 cells and by in vitro synthetic peptide digestion; the RRRRR59→SSSSS mutant is not processed and is biologically inactive.","method":"Cell transfection in Huh-7 and LoVo cells, site-directed mutagenesis, in vitro peptide digestion, furin inhibitors (α1-PDX, ppFurin)","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical in vitro and cell-based processing with mutagenesis, single lab","pmids":["18664504"],"is_preprint":false},{"year":2009,"finding":"PC7 (or a convertase with similar substrate specificity) selectively cleaves the S1 site of pro-BMP4 in Xenopus embryos, whereas furin and PC6 redundantly cleave both S1 and S2 sites; this was established using engineered α1-PDX variants that differentially target PC7 vs. furin/PC6.","method":"Antisense-mediated knockdown in Xenopus oocytes and embryos, engineered furin/PC6/PC7-selective inhibitor (α1-PDX variant), pro-BMP4 processing assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis by selective protease inhibition plus knockdown in two developmental contexts, multiple orthogonal methods","pmids":["19651771"],"is_preprint":false},{"year":2010,"finding":"PC7 zymogen activation occurs primarily in the ER; mature PC7 is partially sulfated and traffics to the cell surface via both a conventional Golgi-dependent pathway and an unconventional brefeldin A- and COPII-independent pathway; cysteines 699 and 704 in the cytosolic tail are palmitoylated but palmitoylation does not control pathway choice; the transmembrane domain of PC7 determines routing to the unconventional pathway, as shown by chimeric Furin-PC7 TMCT swap experiments.","method":"Biochemical subcellular fractionation, electron microscopy, brefeldin A treatment, palmitoylation assay, TMCT chimera construction and trafficking analysis, sulfation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical and cell biology methods including chimeric protein analysis and EM, single lab","pmids":["21075846"],"is_preprint":false},{"year":2010,"finding":"PC7, but not furin, provides a second quality control checkpoint in antigen presentation: PC7-silenced cells with a malfunctioning peptide-loading complex show substantially reduced MHC I surface levels, enhanced MHC I degradation in lysosomes, delayed surface accumulation, and an altered MHC I-presented peptide profile; PC7 is required for liberation of certain MHC I epitopes from exogenously applied peptide precursors.","method":"PC7 siRNA knockdown, MHC I surface staining, mass spectrometry of presented peptides, exogenous peptide loading assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA KD with multiple orthogonal readouts (surface levels, trafficking, mass spectrometry), single lab","pmids":["20164418"],"is_preprint":false},{"year":2011,"finding":"PC7 induces processing of membrane-bound pro-EGF into a ~115-kDa transmembrane form (EGF-115) at an VHPR290↓A motif; site-directed mutagenesis shows Arg290 is not critical, indicating the processing is indirect (via activation of a latent serine and/or cysteine protease by PC7); EGF-115 is more abundant at the cell surface than pro-EGF and is associated with stronger EGFR activation and higher pERK1/2 levels.","method":"PC7 overexpression/knockdown, site-directed mutagenesis of cleavage site, protease inhibitor panel, EGFR/ERK phosphorylation assays, cell surface biotinylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis, protease inhibitor panel, and functional signaling readouts in same study, multiple orthogonal methods","pmids":["21209099"],"is_preprint":false},{"year":2012,"finding":"PC7 internalization from the plasma membrane is mediated by clathrin-coated vesicles; a novel motif between Ala713 and Cys726 in the cytoplasmic tail, containing Pro, Leu, and Cys as essential residues, is necessary and sufficient for PC7 internalization but not for TGN localization.","method":"Clathrin inhibition (hypertonic conditions, Pitstop 2), isolation of clathrin-coated vesicles, cytoplasmic tail deletion and alanine-scanning mutagenesis, antibody uptake and surface biotinylation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical and mutagenesis approaches with multiple deletion and point mutants, single lab with multiple orthogonal methods","pmids":["22294700"],"is_preprint":false},{"year":2013,"finding":"PC7 processes proBDNF into mature BDNF in COS-1 cells and in primary mouse hepatocytes; mature BDNF levels are reduced in hippocampus and amygdala of PC7 KO mice but not PC1/3 KO mice; PC7 KO mice have severely impaired episodic and emotional memory, which is rescued by the TrkB agonist 7,8-dihydroxyflavone, establishing an in vivo role for PC7 in proBDNF processing and cognitive function.","method":"COS-1 cell co-transfection, primary hepatocyte analysis, PC7 KO mouse model, BDNF ELISA/Western blot, behavioral tests, TrkB agonist rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse plus cell-based processing assay plus pharmacological rescue, multiple orthogonal methods in one study","pmids":["24101515"],"is_preprint":false},{"year":2013,"finding":"PCSK7 is essential for zebrafish development; pcsk7 morphant larvae have defects in brain, eye, and otic vesicle, leading to mortality by 7 dpf; PCSK7 contributes to mRNA expression and proteolytic cleavage of TGFβ1a, and tgfβ1a morphants phenocopy pcsk7 morphants.","method":"Morpholino knockdown in zebrafish larvae, homology structural modeling, genome-wide gene expression analysis, TGFβ1a cleavage assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KD with defined phenotype plus biochemical substrate cleavage and phenocopy epistasis, multiple methods","pmids":["24178295"],"is_preprint":false},{"year":2015,"finding":"PC7, Furin, and Pace4 regulate E-cadherin processing during morula compaction and blastocyst formation; loss of these convertases impairs cell-cell adhesion and inner cell mass formation; spatial PC activity profiles mapped by live imaging of transgenic reporter substrate show PC7 is active in partially non-overlapping compartments from Furin.","method":"PC mutant mouse embryo analysis, live imaging of transgenic fluorescent PC reporter, differential inhibitor profiling","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in embryos plus live biosensor imaging and pharmacological dissection, multiple orthogonal methods","pmids":["26416966"],"is_preprint":false},{"year":2018,"finding":"Compartment-specific biosensors reveal that endogenous PC7 is active in distinct vesicles from Furin; a PLC motif in the cytosolic tail of PC7 is dispensable for endosomal activity but required for TGN recycling and for rescuing proActivin-A cleavage in Furin-depleted cells; PC7 complements Furin in Notch1 cleavage independently of PLC-mediated TGN access.","method":"Compartment-targeted biosensors, PC7 PLC-motif mutagenesis, Furin depletion in B16F1 cells, Notch1 and proActivin-A processing assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — novel biosensor technology plus mutagenesis plus substrate processing readouts, multiple orthogonal methods in same study","pmids":["29466742"],"is_preprint":false},{"year":2020,"finding":"PC7 sheds human transferrin receptor 1 (hTfR1) into soluble sTfR1 in endosomes; the EXEXXXL725 motif in the PC7 cytosolic tail is critical for endosomal trafficking and shedding activity; adaptor protein 2 (AP-2) recognizes this motif; Leu-725 enhances PC7 localization to early endosomes; NMR of 14-mer CT peptides reveals that Glu-719, Glu-721, and Leu-725 are on the same face of the helix.","method":"CT deletion and point mutagenesis, hTfR1 shedding assay, immunocytochemistry, AP-2 interaction assay, NMR of CT peptides","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis, NMR structure, protein interaction (AP-2), functional shedding assay, multiple orthogonal methods in one study","pmids":["31915245"],"is_preprint":false},{"year":2020,"finding":"PC7 and Furin shed Cancer Susceptibility Candidate 4 (CASC4) at the KR66↓NS site in acidic endosomes and/or the trans-Golgi network; CASC4 shedding disrupts its anti-migratory role, and the N-terminal PC7/Furin-generated membrane-bound fragment promotes podosome-like structures, enhancing cellular migration and invasion in MDA-MB-231 cells.","method":"Quantitative N-glycoproteomic screen, CASC4 mutagenesis at cleavage site, siRNA knockdown of CASC4, stable CASC4 overexpression, migration/invasion assays, paxillin focal adhesion imaging","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomics substrate discovery plus mutagenesis plus functional cell biology readouts, multiple orthogonal methods","pmids":["32820145"],"is_preprint":false},{"year":2020,"finding":"Wild-type PC7 and its ER-retained forms bind apolipoprotein A-V (apoA-V) and enhance its degradation in acidic lysosomes via a nonenzymatic mechanism; PC7-induced apoA-V degradation is inhibited by bafilomycin A1, chloroquine, and NH4Cl, implicating ER-lysosomal communication; the natural R504H variant enhances Ser505 phosphorylation by Fam20C; the phosphomimetic S505E mutant shows reduced apoA-V degradation; Pcsk7-/- mice on high-fat diet have elevated plasma apoA-V and increased adipocyte LpL activity.","method":"HuH7 cell overexpression, co-immunoprecipitation, lysosomal inhibitor treatments, phosphorylation assay, Pcsk7-/- mouse model, adipocyte LpL activity assay","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell-based and in vivo methods, nonenzymatic binding mechanism established by ER-retained mutants, in vivo validation in KO mice","pmids":["31945259"],"is_preprint":false},{"year":2023,"finding":"Membrane-bound PCSK7 binds apoB100 in the ER and enhances its secretion independent of proteolytic activity; loss of PCSK7 leads to apoB100 degradation via ubiquitination and the proteasome, triggering unfolded protein response, autophagy, and β-oxidation, ultimately reducing hepatic lipid accumulation; Pcsk7-/- mice recover more effectively from diet-induced NAFLD; GalNAc-ASO-mediated hepatic Pcsk7 silencing recapitulates these phenotypes.","method":"Hepatic cell line experiments, co-IP for PC7-apoB100 binding, Pcsk7-/- mouse NAFLD model, GalNAc-ASO knockdown, proteasome inhibition, UPR/autophagy/β-oxidation assays","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP binding, KO mouse model, ASO knockdown, and multiple biochemical pathway assays, orthogonally validated","pmids":["37967646"],"is_preprint":false},{"year":2014,"finding":"PC7 siRNA upregulates HIF-1α protein in normoxic squamous carcinoma cells to levels similar to hypoxia mimetics; this is a post-transcriptional effect occurring at the level of HIF-1α translation (cycloheximide chase); the induction requires IGF-1R signaling and leads to VEGF-A upregulation.","method":"siRNA knockdown of PC7 and furin, Western blot, RT-PCR, cycloheximide chase, IGF-1R signaling inhibitor treatment","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD plus cycloheximide chase plus pharmacological pathway inhibition, single lab","pmids":["24436242"],"is_preprint":false},{"year":2014,"finding":"PC7 and its R504H mutant exhibit similar processing of transferrin receptor-1, proSortilin, and apolipoprotein-F; plasma lipid profiles and insulin/glucose levels are unchanged in PC7 KO mice, indicating that the R504H mutation does not alter PC7 proteolytic activity toward these substrates.","method":"Cell-based processing assays for TfR1, proSortilin, apoF; plasma lipid and metabolic analysis in PC7 KO mice","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple substrate processing assays and KO mouse plasma analysis, single lab, negative result for lipid phenotype","pmids":["25349778"],"is_preprint":false},{"year":2022,"finding":"miR-125a-5p, miR-143-3p, and miR-409-3p directly interact with the 3'-UTR of human PCSK7 mRNA and downregulate PC7 expression; overexpression of miR-125a-5p in Huh7 cells inhibits PC7 protein levels and reduces PC7-mediated cleavage of hTfR1.","method":"Dual-luciferase assay, Western blot, qPCR, transfection of miRNA overexpression vectors, hTfR1 cleavage assay","journal":"Metabolites","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase 3'-UTR validation plus functional substrate processing assay, single lab","pmids":["35888711"],"is_preprint":false},{"year":1999,"finding":"PC8 (PCSK7) endogenously participates in proalbumin processing in HepG2 hepatoma cells alongside PACE4 and furin; antisense-mediated knockdown of PC8 in HepG2 cells results in approximately 30% inhibition of proalbumin-to-albumin processing, demonstrating functional redundancy among these convertases in hepatocytes.","method":"Northern blot of HepG2 expression, co-expression processing assay, stable antisense RNA knockdown, albumin processing Western blot","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antisense knockdown plus co-expression assay, single lab, functionally established substrate in hepatocytes","pmids":["10050053"],"is_preprint":false}],"current_model":"PCSK7 encodes a type-I transmembrane subtilisin/kexin-like serine protease (PC7) that traffics to the cell surface and endosomes via both conventional Golgi-dependent and unconventional COPII-independent routes, with its cytosolic tail motifs (PLC internalization motif and EXEXXXL AP-2-binding motif) governing endosomal recycling and cleavage activity; PC7 cleaves diverse precursor proteins at basic sites (VEGF-C, proBDNF, hepcidin, pro-BMP4 S1 site, CASC4, gp160, proalbumin, pro-NGF) and also acts non-enzymatically by binding apoB100 in the ER to promote its secretion and by chaperoning apoA-V to lysosomes for degradation, thereby regulating hepatic triglyceride metabolism and NAFLD; additional roles include MHC I antigen presentation quality control, EGF receptor activation via indirect pro-EGF processing, and regulation of cognitive function through hippocampal proBDNF maturation."},"narrative":{"mechanistic_narrative":"PCSK7 encodes PC7, a type-I membrane-bound subtilisin/kexin-like serine proprotein convertase that is synthesized as a glycosylated zymogen, autoactivated by removal of its RAKR-ending prosegment principally in the ER, and traffics to the cell surface and endosomes through both a conventional Golgi-dependent route and an unconventional brefeldin A- and COPII-independent route specified by its transmembrane domain [PMID:8622945, PMID:9242622, PMID:21075846]. Its own prosegment is a potent competitive inhibitor whose C-terminal helical decapeptide retains nanomolar inhibitory activity dependent on a P1 Arg [PMID:10567353, PMID:10715106]. PC7 cleaves a broad set of precursors at basic motifs to control diverse processes: it processes proVEGF-C to drive angiogenesis and tumor growth [PMID:12782675], preprohepcidin to its active hormone [PMID:18664504], the S1 site of pro-BMP4 [PMID:19651771], and proBDNF to mature BDNF, with PC7 knockout mice showing reduced hippocampal/amygdalar BDNF and impaired memory rescuable by a TrkB agonist [PMID:24101515]. Substrate selection is conformation-dependent, as PC7 fails to cleave integrin α-subunit precursors despite appropriate sequences [PMID:10657249], and several substrates are shared redundantly with Furin, PACE4 and PC5 (proalbumin, E-cadherin, gp160) [PMID:10050053, PMID:26416966, PMID:9094426]. Compartmentalized activity is governed by cytosolic-tail motifs: a clathrin/AP-2 internalization motif and the EXEXXXL motif direct endosomal recycling and shedding of substrates such as transferrin receptor-1 and CASC4, while a PLC motif controls TGN recycling required for proActivin-A processing [PMID:22294700, PMID:31915245, PMID:32820145, PMID:29466742]. PC7 also acts non-enzymatically in hepatic lipid metabolism, binding apoB100 in the ER to promote its secretion and chaperoning apoA-V to lysosomal degradation, such that Pcsk7 loss reduces hepatic lipid accumulation and improves recovery from NAFLD [PMID:37967646, PMID:31945259]. Additional roles include a second quality-control checkpoint in MHC class I antigen presentation [PMID:20164418] and indirect activation of pro-EGF processing that potentiates EGFR/ERK signaling [PMID:21209099].","teleology":[{"year":1996,"claim":"Established PC7 as a distinct, most-divergent mammalian proprotein convertase, defining the molecular substrate for all subsequent functional study.","evidence":"cDNA cloning, phylogenetics, Northern blot and chromosomal mapping","pmids":["8622945"],"confidence":"High","gaps":["No enzymatic activity or substrate demonstrated at this stage","Subcellular trafficking unknown"]},{"year":1997,"claim":"Defined PC7 as a Ca2+-dependent serine proteinase activated in the ER with furin-like but distinct substrate preferences, answering whether it is catalytically active and on what motifs.","evidence":"Recombinant overexpression with fluorogenic and synthetic peptide cleavage assays","pmids":["9242622","9094426"],"confidence":"High","gaps":["Physiological substrates not yet identified","gp160 cleavage shown only in overexpression contexts"]},{"year":2000,"claim":"Characterized the PC7 prosegment as a folded, nanomolar competitive autoinhibitor, defining the enzyme's intrinsic regulatory mechanism and a tool for inhibition.","evidence":"In vitro inhibition assays, mutagenesis, NMR structure of the prosegment peptide","pmids":["10567353","10715106"],"confidence":"High","gaps":["Endogenous timing/location of prosegment release in vivo not resolved"]},{"year":2003,"claim":"Demonstrated bona fide physiological precursor processing by PC7, showing proVEGF-C cleavage is required for angiogenesis and tumor growth and resolving its in vivo relevance.","evidence":"Cell-based processing in furin-deficient cells, in vitro digestion, cleavage-site mutagenesis, nude-mouse tumor model","pmids":["12782675"],"confidence":"High","gaps":["Redundancy with furin/PC5 leaves PC7-specific contribution in vivo unquantified"]},{"year":2009,"claim":"Extended the PC7 substrate repertoire to hepcidin and pro-BMP4, showing both redundant and site-selective processing among convertases.","evidence":"Cell transfection, mutagenesis, in vitro peptide digestion, selective α1-PDX variants, Xenopus knockdown","pmids":["18664504","19651771"],"confidence":"High","gaps":["Relative contribution of PC7 vs furin/PC5 in physiological tissue not established"]},{"year":2010,"claim":"Resolved PC7 trafficking, showing ER activation followed by routing to surface/endosomes via conventional and unconventional TMD-determined pathways, and uncovered non-redundant roles in MHC I antigen presentation.","evidence":"Subcellular fractionation, EM, BFA treatment, TMCT chimeras, siRNA knockdown with MHC I surface/MS readouts","pmids":["21075846","20164418"],"confidence":"High","gaps":["Molecular determinants of unconventional secretion beyond TMD unknown","MHC I peptide-trimming protease activity vs adaptor role not fully separated"]},{"year":2011,"claim":"Showed PC7 activates pro-EGF processing indirectly via a downstream protease, linking it to EGFR/ERK signaling rather than direct cleavage.","evidence":"Overexpression/knockdown, cleavage-site mutagenesis, protease inhibitor panel, EGFR/ERK phosphorylation, surface biotinylation","pmids":["21209099"],"confidence":"High","gaps":["Identity of the latent protease activated by PC7 not determined"]},{"year":2013,"claim":"Established an in vivo neurological function: PC7 maturation of proBDNF supports hippocampal BDNF and memory, with developmental roles confirmed in zebrafish.","evidence":"Cell processing assays, PC7 KO mouse behavior with TrkB agonist rescue, zebrafish morpholino knockdown with TGFβ1a epistasis","pmids":["24101515","24178295"],"confidence":"High","gaps":["Cell-type and circuit basis of memory phenotype not dissected","Direct vs indirect TGFβ1a processing in zebrafish not fully separated"]},{"year":2018,"claim":"Defined cytosolic-tail motifs (clathrin internalization, PLC, EXEXXXL/AP-2) that compartmentalize PC7 activity in endosomes vs TGN, controlling substrate-specific processing and shedding.","evidence":"Clathrin inhibition, coated-vesicle isolation, tail mutagenesis, compartment biosensors, AP-2 interaction, NMR of tail peptides, TfR1/CASC4/proActivin-A/Notch1 assays","pmids":["22294700","29466742","31915245","32820145"],"confidence":"High","gaps":["How compartment choice is regulated dynamically in physiology unclear","Functional consequences of TfR1/CASC4 shedding in vivo not established"]},{"year":2023,"claim":"Revealed non-enzymatic roles of PC7 in hepatic lipid metabolism—apoB100 binding/secretion and apoA-V lysosomal degradation—implicating PCSK7 in NAFLD.","evidence":"Co-IP binding, ER-retained mutants, lysosomal inhibitors, phosphorylation assays, Pcsk7-/- mice and GalNAc-ASO knockdown with UPR/autophagy/β-oxidation readouts","pmids":["37967646","31945259"],"confidence":"High","gaps":["Structural basis of apoB100/apoA-V binding undefined","Relationship between catalytic and chaperone functions in liver not integrated"]},{"year":null,"claim":"How PC7's catalytic, chaperone, and trafficking activities are coordinated, and how the R504H/regulatory variants modulate human disease, remains unresolved.","evidence":"Open question synthesized across the timeline","pmids":[],"confidence":"Medium","gaps":["No causative Mendelian disease link established","R504H reported to alter apoA-V handling but not classical substrate processing, leaving its physiological role ambiguous"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,8,9,10,15,19,20]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,8,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[21,22]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,11,21,22]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,13,14]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[18,19,20]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11,18]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[12,21]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,8,9,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[21,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[11,14,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13]}],"complexes":[],"partners":["APOB100","APOA-V","AP-2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16549","full_name":"Proprotein convertase subtilisin/kexin type 7","aliases":["Lymphoma proprotein convertase","Prohormone convertase 7","Proprotein convertase 7","PC7","Proprotein convertase 8","PC8","hPC8","Subtilisin/kexin-like protease PC7"],"length_aa":785,"mass_kda":86.2,"function":"Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. 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HDL-Cholesterol and Triglycerides.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34207761","citation_count":11,"is_preprint":false},{"pmid":"39273358","id":"PMC_39273358","title":"Quercetin Mitigates Lysophosphatidylcholine (LPC)-Induced Neutrophil Extracellular Traps (NETs) Formation through Inhibiting the P2X7R/P38MAPK/NOX2 Pathway.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39273358","citation_count":11,"is_preprint":false},{"pmid":"24859040","id":"PMC_24859040","title":"Metallothionein-III increases ADAM10 activity in association with furin, PC7, and PKCα during non-amyloidogenic processing.","date":"2014","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/24859040","citation_count":10,"is_preprint":false},{"pmid":"25349778","id":"PMC_25349778","title":"Is there a link between proprotein convertase PC7 activity and human lipid homeostasis?","date":"2014","source":"FEBS open 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31915245","citation_count":8,"is_preprint":false},{"pmid":"17007739","id":"PMC_17007739","title":"Inhibitory effects of cariporide on LPC-induced expression of ICAM-1 and adhesion of monocytes to smooth muscle cells in vitro.","date":"2006","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/17007739","citation_count":8,"is_preprint":false},{"pmid":"16805103","id":"PMC_16805103","title":"LPC cepstral distortion measure for protein sequence comparison.","date":"2006","source":"IEEE transactions on nanobioscience","url":"https://pubmed.ncbi.nlm.nih.gov/16805103","citation_count":8,"is_preprint":false},{"pmid":"445451","id":"PMC_445451","title":"Temporary disappearance (\"eclipse\") of LPC-1 plasmacytoma M component synthesis following tumor cell transfer.","date":"1979","source":"Cancer 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Associated with Obesity, Triglycerides Level and Fatty Liver Index in a General Population without Medication.","date":"2021","source":"Journal of atherosclerosis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/34565765","citation_count":5,"is_preprint":false},{"pmid":"30618984","id":"PMC_30618984","title":"The N1-N2-LPC Pattern in Processing Advertising Pictorial Metaphors: An ERP Study.","date":"2018","source":"Frontiers in psychology","url":"https://pubmed.ncbi.nlm.nih.gov/30618984","citation_count":5,"is_preprint":false},{"pmid":"9597003","id":"PMC_9597003","title":"Senescent WI-38 fibroblasts overexpress LPC-1, a putative transmembrane shock protein.","date":"1998","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/9597003","citation_count":5,"is_preprint":false},{"pmid":"1848940","id":"PMC_1848940","title":"Nitroarginine does not inhibit lysophosphatidylcholine (LPC)-induced vascular relaxation and accumulation of cyclic 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phylogenetic analysis places it as the most divergent mammalian convertase and closest to yeast kexin/krp convertases.\",\n      \"method\": \"cDNA cloning, sequence analysis, Northern blot, in situ hybridization, chromosomal linkage mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — foundational biochemical characterization with multiple orthogonal methods (cDNA sequencing, phylogenetics, Northern blot, chromosomal mapping), replicated across subsequent studies\",\n      \"pmids\": [\"8622945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Rat PC7 is synthesized as a 101-kDa glycosylated zymogen, processed to an 89-kDa mature form in the endoplasmic reticulum; enzymatic assays show pH optimum, Ca2+ dependence, and cleavage specificity largely similar to furin but with some kexin-like substrate preferences; PC7 correctly processes peptides containing the pro-PTH and pro-PC4 processing sites but not a pro-EGF site.\",\n      \"method\": \"Vaccinia-virus recombinant overexpression in BSC40 cells, fluorogenic peptide substrate assays, synthetic peptide cleavage, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic characterization with multiple substrates and mutants, foundational biochemistry paper\",\n      \"pmids\": [\"9242622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PC7 cleaves HIV-1 gp160 into gp120/gp41 in a cell-type-specific manner (active in BSC40 and T4 lymphocyte contexts) and in vitro on a synthetic peptide spanning the cleavage site; both furin and PC7 are upregulated 5–10-fold in HIV-replication-promoting activated T4 lymphocytes.\",\n      \"method\": \"Co-expression in BSC40 and AtT20 cells, in vitro gp160 cleavage assay, RT-PCR\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based co-expression plus in vitro assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"9094426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Purified recombinant prosegments of furin and PC7 are potent, moderately selective inhibitors of their parent enzymes in vitro (inhibiting fluorogenic peptide cleavage and HIV gp160 processing); short C-terminal decapeptides of the prosegments retain inhibitory activity with the P1 Arg being essential; expressed ex vivo via vaccinia virus, the prosegments inhibit processing of NGF and BDNF in trans.\",\n      \"method\": \"In vitro fluorogenic peptide assay, recombinant prosegment purification, vaccinia virus ex vivo expression, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro inhibition with mutagenesis (P1 Arg requirement) and ex vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"10567353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PC7 overexpression increases APPα secretion and reduces Aβ40/42 levels in HEK293 cells; this effect is blocked by α1-PDX (a proprotein convertase inhibitor), indicating PC7 participates in the constitutive α-secretase pathway for APP processing.\",\n      \"method\": \"Transient transfection in HEK293 cells, ELISA/immunoassay for APPα and Aβ40/42, α1-PDX inhibitor\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression and pharmacological inhibition in human cells, single lab, two complementary approaches\",\n      \"pmids\": [\"10537065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Furin and PC7 mRNAs and proteins co-localize with NGF in Schwann cells, macrophages, and perivascular smooth muscle cells of injured sciatic nerve, and both convertases are upregulated after nerve lesion, suggesting a role in pro-NGF processing.\",\n      \"method\": \"Northern blot, immunocytochemistry, in situ hybridization on nerve explants and in vivo injury model\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization and co-regulation data without direct processing assay, replicated in vivo and ex vivo\",\n      \"pmids\": [\"9888313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PC7 does not process integrin α-subunit precursors (pro-α5, α6, αv) either in vitro or ex vivo in LoVo cells, despite similar cleavage-site sequences to known PC7 substrates, indicating that substrate conformation determines PC7 accessibility.\",\n      \"method\": \"In vitro cleavage assay with recombinant PC7, LoVo cell co-expression (ex vivo), Western blot\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro and ex vivo assays, negative result explicitly established with both methods, single lab\",\n      \"pmids\": [\"10657249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A 24-residue C-terminal peptide of the PC7 prosegment (residues 81p–104p) inhibits PC7 with Ki = 7 nM and adopts a helical conformation in solution; the folded structure is proposed to underlie its potency as a competitive inhibitor.\",\n      \"method\": \"Enzyme inhibition assay, NMR structure determination with NOE restraints\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure by NMR plus functional Ki measurement in the same study, single lab but two orthogonal methods\",\n      \"pmids\": [\"10715106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Furin, PC5, and PC7 cleave proVEGF-C within the dibasic motif HSIIRR227↓SL to generate mature VEGF-C; this processing is required for VEGF-C-induced angiogenesis, lymphangiogenesis, and tumor growth in nude mice.\",\n      \"method\": \"Co-transfection in furin-deficient LoVo cells, in vitro fluorogenic peptide digestion, subcutaneous CHO cell injection into nude mice, cleavage-site mutagenesis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cell-based processing assay, in vitro biochemical assay, site-directed mutagenesis, and in vivo tumorigenesis model, multiple orthogonal methods\",\n      \"pmids\": [\"12782675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PC7 (along with Furin, PACE4, and PC5) cleaves the preprohepcidin convertase site RRRRR59↓DT to generate active hepcidin; cleavage was demonstrated in Huh-7 cells and by in vitro synthetic peptide digestion; the RRRRR59→SSSSS mutant is not processed and is biologically inactive.\",\n      \"method\": \"Cell transfection in Huh-7 and LoVo cells, site-directed mutagenesis, in vitro peptide digestion, furin inhibitors (α1-PDX, ppFurin)\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical in vitro and cell-based processing with mutagenesis, single lab\",\n      \"pmids\": [\"18664504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PC7 (or a convertase with similar substrate specificity) selectively cleaves the S1 site of pro-BMP4 in Xenopus embryos, whereas furin and PC6 redundantly cleave both S1 and S2 sites; this was established using engineered α1-PDX variants that differentially target PC7 vs. furin/PC6.\",\n      \"method\": \"Antisense-mediated knockdown in Xenopus oocytes and embryos, engineered furin/PC6/PC7-selective inhibitor (α1-PDX variant), pro-BMP4 processing assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis by selective protease inhibition plus knockdown in two developmental contexts, multiple orthogonal methods\",\n      \"pmids\": [\"19651771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PC7 zymogen activation occurs primarily in the ER; mature PC7 is partially sulfated and traffics to the cell surface via both a conventional Golgi-dependent pathway and an unconventional brefeldin A- and COPII-independent pathway; cysteines 699 and 704 in the cytosolic tail are palmitoylated but palmitoylation does not control pathway choice; the transmembrane domain of PC7 determines routing to the unconventional pathway, as shown by chimeric Furin-PC7 TMCT swap experiments.\",\n      \"method\": \"Biochemical subcellular fractionation, electron microscopy, brefeldin A treatment, palmitoylation assay, TMCT chimera construction and trafficking analysis, sulfation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical and cell biology methods including chimeric protein analysis and EM, single lab\",\n      \"pmids\": [\"21075846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PC7, but not furin, provides a second quality control checkpoint in antigen presentation: PC7-silenced cells with a malfunctioning peptide-loading complex show substantially reduced MHC I surface levels, enhanced MHC I degradation in lysosomes, delayed surface accumulation, and an altered MHC I-presented peptide profile; PC7 is required for liberation of certain MHC I epitopes from exogenously applied peptide precursors.\",\n      \"method\": \"PC7 siRNA knockdown, MHC I surface staining, mass spectrometry of presented peptides, exogenous peptide loading assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA KD with multiple orthogonal readouts (surface levels, trafficking, mass spectrometry), single lab\",\n      \"pmids\": [\"20164418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PC7 induces processing of membrane-bound pro-EGF into a ~115-kDa transmembrane form (EGF-115) at an VHPR290↓A motif; site-directed mutagenesis shows Arg290 is not critical, indicating the processing is indirect (via activation of a latent serine and/or cysteine protease by PC7); EGF-115 is more abundant at the cell surface than pro-EGF and is associated with stronger EGFR activation and higher pERK1/2 levels.\",\n      \"method\": \"PC7 overexpression/knockdown, site-directed mutagenesis of cleavage site, protease inhibitor panel, EGFR/ERK phosphorylation assays, cell surface biotinylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis, protease inhibitor panel, and functional signaling readouts in same study, multiple orthogonal methods\",\n      \"pmids\": [\"21209099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PC7 internalization from the plasma membrane is mediated by clathrin-coated vesicles; a novel motif between Ala713 and Cys726 in the cytoplasmic tail, containing Pro, Leu, and Cys as essential residues, is necessary and sufficient for PC7 internalization but not for TGN localization.\",\n      \"method\": \"Clathrin inhibition (hypertonic conditions, Pitstop 2), isolation of clathrin-coated vesicles, cytoplasmic tail deletion and alanine-scanning mutagenesis, antibody uptake and surface biotinylation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical and mutagenesis approaches with multiple deletion and point mutants, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22294700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PC7 processes proBDNF into mature BDNF in COS-1 cells and in primary mouse hepatocytes; mature BDNF levels are reduced in hippocampus and amygdala of PC7 KO mice but not PC1/3 KO mice; PC7 KO mice have severely impaired episodic and emotional memory, which is rescued by the TrkB agonist 7,8-dihydroxyflavone, establishing an in vivo role for PC7 in proBDNF processing and cognitive function.\",\n      \"method\": \"COS-1 cell co-transfection, primary hepatocyte analysis, PC7 KO mouse model, BDNF ELISA/Western blot, behavioral tests, TrkB agonist rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse plus cell-based processing assay plus pharmacological rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24101515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PCSK7 is essential for zebrafish development; pcsk7 morphant larvae have defects in brain, eye, and otic vesicle, leading to mortality by 7 dpf; PCSK7 contributes to mRNA expression and proteolytic cleavage of TGFβ1a, and tgfβ1a morphants phenocopy pcsk7 morphants.\",\n      \"method\": \"Morpholino knockdown in zebrafish larvae, homology structural modeling, genome-wide gene expression analysis, TGFβ1a cleavage assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KD with defined phenotype plus biochemical substrate cleavage and phenocopy epistasis, multiple methods\",\n      \"pmids\": [\"24178295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PC7, Furin, and Pace4 regulate E-cadherin processing during morula compaction and blastocyst formation; loss of these convertases impairs cell-cell adhesion and inner cell mass formation; spatial PC activity profiles mapped by live imaging of transgenic reporter substrate show PC7 is active in partially non-overlapping compartments from Furin.\",\n      \"method\": \"PC mutant mouse embryo analysis, live imaging of transgenic fluorescent PC reporter, differential inhibitor profiling\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in embryos plus live biosensor imaging and pharmacological dissection, multiple orthogonal methods\",\n      \"pmids\": [\"26416966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Compartment-specific biosensors reveal that endogenous PC7 is active in distinct vesicles from Furin; a PLC motif in the cytosolic tail of PC7 is dispensable for endosomal activity but required for TGN recycling and for rescuing proActivin-A cleavage in Furin-depleted cells; PC7 complements Furin in Notch1 cleavage independently of PLC-mediated TGN access.\",\n      \"method\": \"Compartment-targeted biosensors, PC7 PLC-motif mutagenesis, Furin depletion in B16F1 cells, Notch1 and proActivin-A processing assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — novel biosensor technology plus mutagenesis plus substrate processing readouts, multiple orthogonal methods in same study\",\n      \"pmids\": [\"29466742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PC7 sheds human transferrin receptor 1 (hTfR1) into soluble sTfR1 in endosomes; the EXEXXXL725 motif in the PC7 cytosolic tail is critical for endosomal trafficking and shedding activity; adaptor protein 2 (AP-2) recognizes this motif; Leu-725 enhances PC7 localization to early endosomes; NMR of 14-mer CT peptides reveals that Glu-719, Glu-721, and Leu-725 are on the same face of the helix.\",\n      \"method\": \"CT deletion and point mutagenesis, hTfR1 shedding assay, immunocytochemistry, AP-2 interaction assay, NMR of CT peptides\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis, NMR structure, protein interaction (AP-2), functional shedding assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31915245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PC7 and Furin shed Cancer Susceptibility Candidate 4 (CASC4) at the KR66↓NS site in acidic endosomes and/or the trans-Golgi network; CASC4 shedding disrupts its anti-migratory role, and the N-terminal PC7/Furin-generated membrane-bound fragment promotes podosome-like structures, enhancing cellular migration and invasion in MDA-MB-231 cells.\",\n      \"method\": \"Quantitative N-glycoproteomic screen, CASC4 mutagenesis at cleavage site, siRNA knockdown of CASC4, stable CASC4 overexpression, migration/invasion assays, paxillin focal adhesion imaging\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomics substrate discovery plus mutagenesis plus functional cell biology readouts, multiple orthogonal methods\",\n      \"pmids\": [\"32820145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wild-type PC7 and its ER-retained forms bind apolipoprotein A-V (apoA-V) and enhance its degradation in acidic lysosomes via a nonenzymatic mechanism; PC7-induced apoA-V degradation is inhibited by bafilomycin A1, chloroquine, and NH4Cl, implicating ER-lysosomal communication; the natural R504H variant enhances Ser505 phosphorylation by Fam20C; the phosphomimetic S505E mutant shows reduced apoA-V degradation; Pcsk7-/- mice on high-fat diet have elevated plasma apoA-V and increased adipocyte LpL activity.\",\n      \"method\": \"HuH7 cell overexpression, co-immunoprecipitation, lysosomal inhibitor treatments, phosphorylation assay, Pcsk7-/- mouse model, adipocyte LpL activity assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell-based and in vivo methods, nonenzymatic binding mechanism established by ER-retained mutants, in vivo validation in KO mice\",\n      \"pmids\": [\"31945259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Membrane-bound PCSK7 binds apoB100 in the ER and enhances its secretion independent of proteolytic activity; loss of PCSK7 leads to apoB100 degradation via ubiquitination and the proteasome, triggering unfolded protein response, autophagy, and β-oxidation, ultimately reducing hepatic lipid accumulation; Pcsk7-/- mice recover more effectively from diet-induced NAFLD; GalNAc-ASO-mediated hepatic Pcsk7 silencing recapitulates these phenotypes.\",\n      \"method\": \"Hepatic cell line experiments, co-IP for PC7-apoB100 binding, Pcsk7-/- mouse NAFLD model, GalNAc-ASO knockdown, proteasome inhibition, UPR/autophagy/β-oxidation assays\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP binding, KO mouse model, ASO knockdown, and multiple biochemical pathway assays, orthogonally validated\",\n      \"pmids\": [\"37967646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PC7 siRNA upregulates HIF-1α protein in normoxic squamous carcinoma cells to levels similar to hypoxia mimetics; this is a post-transcriptional effect occurring at the level of HIF-1α translation (cycloheximide chase); the induction requires IGF-1R signaling and leads to VEGF-A upregulation.\",\n      \"method\": \"siRNA knockdown of PC7 and furin, Western blot, RT-PCR, cycloheximide chase, IGF-1R signaling inhibitor treatment\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD plus cycloheximide chase plus pharmacological pathway inhibition, single lab\",\n      \"pmids\": [\"24436242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PC7 and its R504H mutant exhibit similar processing of transferrin receptor-1, proSortilin, and apolipoprotein-F; plasma lipid profiles and insulin/glucose levels are unchanged in PC7 KO mice, indicating that the R504H mutation does not alter PC7 proteolytic activity toward these substrates.\",\n      \"method\": \"Cell-based processing assays for TfR1, proSortilin, apoF; plasma lipid and metabolic analysis in PC7 KO mice\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple substrate processing assays and KO mouse plasma analysis, single lab, negative result for lipid phenotype\",\n      \"pmids\": [\"25349778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-125a-5p, miR-143-3p, and miR-409-3p directly interact with the 3'-UTR of human PCSK7 mRNA and downregulate PC7 expression; overexpression of miR-125a-5p in Huh7 cells inhibits PC7 protein levels and reduces PC7-mediated cleavage of hTfR1.\",\n      \"method\": \"Dual-luciferase assay, Western blot, qPCR, transfection of miRNA overexpression vectors, hTfR1 cleavage assay\",\n      \"journal\": \"Metabolites\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase 3'-UTR validation plus functional substrate processing assay, single lab\",\n      \"pmids\": [\"35888711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PC8 (PCSK7) endogenously participates in proalbumin processing in HepG2 hepatoma cells alongside PACE4 and furin; antisense-mediated knockdown of PC8 in HepG2 cells results in approximately 30% inhibition of proalbumin-to-albumin processing, demonstrating functional redundancy among these convertases in hepatocytes.\",\n      \"method\": \"Northern blot of HepG2 expression, co-expression processing assay, stable antisense RNA knockdown, albumin processing Western blot\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antisense knockdown plus co-expression assay, single lab, functionally established substrate in hepatocytes\",\n      \"pmids\": [\"10050053\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PCSK7 encodes a type-I transmembrane subtilisin/kexin-like serine protease (PC7) that traffics to the cell surface and endosomes via both conventional Golgi-dependent and unconventional COPII-independent routes, with its cytosolic tail motifs (PLC internalization motif and EXEXXXL AP-2-binding motif) governing endosomal recycling and cleavage activity; PC7 cleaves diverse precursor proteins at basic sites (VEGF-C, proBDNF, hepcidin, pro-BMP4 S1 site, CASC4, gp160, proalbumin, pro-NGF) and also acts non-enzymatically by binding apoB100 in the ER to promote its secretion and by chaperoning apoA-V to lysosomes for degradation, thereby regulating hepatic triglyceride metabolism and NAFLD; additional roles include MHC I antigen presentation quality control, EGF receptor activation via indirect pro-EGF processing, and regulation of cognitive function through hippocampal proBDNF maturation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PCSK7 encodes PC7, a type-I membrane-bound subtilisin/kexin-like serine proprotein convertase that is synthesized as a glycosylated zymogen, autoactivated by removal of its RAKR-ending prosegment principally in the ER, and traffics to the cell surface and endosomes through both a conventional Golgi-dependent route and an unconventional brefeldin A- and COPII-independent route specified by its transmembrane domain [#0, #1, #11]. Its own prosegment is a potent competitive inhibitor whose C-terminal helical decapeptide retains nanomolar inhibitory activity dependent on a P1 Arg [#3, #7]. PC7 cleaves a broad set of precursors at basic motifs to control diverse processes: it processes proVEGF-C to drive angiogenesis and tumor growth [#8], preprohepcidin to its active hormone [#9], the S1 site of pro-BMP4 [#10], and proBDNF to mature BDNF, with PC7 knockout mice showing reduced hippocampal/amygdalar BDNF and impaired memory rescuable by a TrkB agonist [#15]. Substrate selection is conformation-dependent, as PC7 fails to cleave integrin α-subunit precursors despite appropriate sequences [#6], and several substrates are shared redundantly with Furin, PACE4 and PC5 (proalbumin, E-cadherin, gp160) [#26, #17, #2]. Compartmentalized activity is governed by cytosolic-tail motifs: a clathrin/AP-2 internalization motif and the EXEXXXL motif direct endosomal recycling and shedding of substrates such as transferrin receptor-1 and CASC4, while a PLC motif controls TGN recycling required for proActivin-A processing [#14, #19, #20, #18]. PC7 also acts non-enzymatically in hepatic lipid metabolism, binding apoB100 in the ER to promote its secretion and chaperoning apoA-V to lysosomal degradation, such that Pcsk7 loss reduces hepatic lipid accumulation and improves recovery from NAFLD [#22, #21]. Additional roles include a second quality-control checkpoint in MHC class I antigen presentation [#12] and indirect activation of pro-EGF processing that potentiates EGFR/ERK signaling [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established PC7 as a distinct, most-divergent mammalian proprotein convertase, defining the molecular substrate for all subsequent functional study.\",\n      \"evidence\": \"cDNA cloning, phylogenetics, Northern blot and chromosomal mapping\",\n      \"pmids\": [\"8622945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No enzymatic activity or substrate demonstrated at this stage\", \"Subcellular trafficking unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined PC7 as a Ca2+-dependent serine proteinase activated in the ER with furin-like but distinct substrate preferences, answering whether it is catalytically active and on what motifs.\",\n      \"evidence\": \"Recombinant overexpression with fluorogenic and synthetic peptide cleavage assays\",\n      \"pmids\": [\"9242622\", \"9094426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates not yet identified\", \"gp160 cleavage shown only in overexpression contexts\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Characterized the PC7 prosegment as a folded, nanomolar competitive autoinhibitor, defining the enzyme's intrinsic regulatory mechanism and a tool for inhibition.\",\n      \"evidence\": \"In vitro inhibition assays, mutagenesis, NMR structure of the prosegment peptide\",\n      \"pmids\": [\"10567353\", \"10715106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous timing/location of prosegment release in vivo not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated bona fide physiological precursor processing by PC7, showing proVEGF-C cleavage is required for angiogenesis and tumor growth and resolving its in vivo relevance.\",\n      \"evidence\": \"Cell-based processing in furin-deficient cells, in vitro digestion, cleavage-site mutagenesis, nude-mouse tumor model\",\n      \"pmids\": [\"12782675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with furin/PC5 leaves PC7-specific contribution in vivo unquantified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the PC7 substrate repertoire to hepcidin and pro-BMP4, showing both redundant and site-selective processing among convertases.\",\n      \"evidence\": \"Cell transfection, mutagenesis, in vitro peptide digestion, selective α1-PDX variants, Xenopus knockdown\",\n      \"pmids\": [\"18664504\", \"19651771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of PC7 vs furin/PC5 in physiological tissue not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved PC7 trafficking, showing ER activation followed by routing to surface/endosomes via conventional and unconventional TMD-determined pathways, and uncovered non-redundant roles in MHC I antigen presentation.\",\n      \"evidence\": \"Subcellular fractionation, EM, BFA treatment, TMCT chimeras, siRNA knockdown with MHC I surface/MS readouts\",\n      \"pmids\": [\"21075846\", \"20164418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants of unconventional secretion beyond TMD unknown\", \"MHC I peptide-trimming protease activity vs adaptor role not fully separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed PC7 activates pro-EGF processing indirectly via a downstream protease, linking it to EGFR/ERK signaling rather than direct cleavage.\",\n      \"evidence\": \"Overexpression/knockdown, cleavage-site mutagenesis, protease inhibitor panel, EGFR/ERK phosphorylation, surface biotinylation\",\n      \"pmids\": [\"21209099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the latent protease activated by PC7 not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established an in vivo neurological function: PC7 maturation of proBDNF supports hippocampal BDNF and memory, with developmental roles confirmed in zebrafish.\",\n      \"evidence\": \"Cell processing assays, PC7 KO mouse behavior with TrkB agonist rescue, zebrafish morpholino knockdown with TGFβ1a epistasis\",\n      \"pmids\": [\"24101515\", \"24178295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type and circuit basis of memory phenotype not dissected\", \"Direct vs indirect TGFβ1a processing in zebrafish not fully separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined cytosolic-tail motifs (clathrin internalization, PLC, EXEXXXL/AP-2) that compartmentalize PC7 activity in endosomes vs TGN, controlling substrate-specific processing and shedding.\",\n      \"evidence\": \"Clathrin inhibition, coated-vesicle isolation, tail mutagenesis, compartment biosensors, AP-2 interaction, NMR of tail peptides, TfR1/CASC4/proActivin-A/Notch1 assays\",\n      \"pmids\": [\"22294700\", \"29466742\", \"31915245\", \"32820145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How compartment choice is regulated dynamically in physiology unclear\", \"Functional consequences of TfR1/CASC4 shedding in vivo not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed non-enzymatic roles of PC7 in hepatic lipid metabolism—apoB100 binding/secretion and apoA-V lysosomal degradation—implicating PCSK7 in NAFLD.\",\n      \"evidence\": \"Co-IP binding, ER-retained mutants, lysosomal inhibitors, phosphorylation assays, Pcsk7-/- mice and GalNAc-ASO knockdown with UPR/autophagy/β-oxidation readouts\",\n      \"pmids\": [\"37967646\", \"31945259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of apoB100/apoA-V binding undefined\", \"Relationship between catalytic and chaperone functions in liver not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PC7's catalytic, chaperone, and trafficking activities are coordinated, and how the R504H/regulatory variants modulate human disease, remains unresolved.\",\n      \"evidence\": \"Open question synthesized across the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No causative Mendelian disease link established\", \"R504H reported to alter apoA-V handling but not classical substrate processing, leaving its physiological role ambiguous\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 8, 9, 10, 15, 19, 20]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 8, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [21, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 11, 21, 22]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 13, 14]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [18, 19, 20]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11, 18]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [12, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 8, 9, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [21, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [11, 14, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"apoB100\", \"apoA-V\", \"AP-2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}