{"gene":"PCSK7","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":1996,"finding":"PC7 (PCSK7) was identified as a novel type I membrane-bound serine proteinase of the subtilisin/kexin family, synthesized as a prepro-PC with signal peptide, prosegment ending in cleavable RAKR, and a 747-amino acid mature form; phylogenetic analysis placed it as the most divergent mammalian convertase and closest to yeast kexin.","method":"cDNA cloning, Northern blot, in situ hybridization, linkage analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — original cloning and structural characterization with multiple orthogonal methods; foundational paper with 221 citations","pmids":["8622945"],"is_preprint":false},{"year":1997,"finding":"Rat PC7 is synthesized as a glycosylated zymogen (101 kDa) processed to mature PC7 (89 kDa) in the ER; it has enzymatic activity on fluorogenic peptidyl substrates with pH optimum and Ca2+ dependence similar to furin, correctly processes pro-PTH and pro-PC4 peptides, but not pro-EGF peptide.","method":"Vaccinia virus overexpression in BSC40 cells, enzymatic activity assays with fluorogenic substrates, in vitro peptide cleavage assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic characterization with multiple substrates; first biochemical description of PC7 activity","pmids":["9242622"],"is_preprint":false},{"year":1997,"finding":"PC7 can cleave HIV envelope glycoprotein gp160 into gp120/gp41 in a cell-type-specific manner, similar to furin, and is expressed at higher levels in activated T4 lymphocytes; demonstrated using cell-based co-expression assays and in vitro cleavage of synthetic peptides.","method":"RT-PCR, cell-based co-expression assay in BSC40 and AtT20 cells, in vitro synthetic peptide cleavage","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based and in vitro assays, single lab","pmids":["9094426"],"is_preprint":false},{"year":1999,"finding":"The prosegment of PC7 acts as a potent inhibitor of PC7 enzyme activity; recombinant bacterial prosegments inhibit PC7 in vitro and, when expressed via vaccinia virus ex vivo, inhibit processing of NGF and BDNF precursors in trans.","method":"Recombinant prosegment purification, in vitro fluorogenic peptide assays, ex vivo vaccinia virus expression, Western blotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro inhibition assays combined with ex vivo functional validation","pmids":["10567353"],"is_preprint":false},{"year":1999,"finding":"PC7 contributes to the alpha-secretase pathway for beta-amyloid precursor protein (betaAPP): overexpression of PC7 increases APPalpha secretion and reduces Abeta40/42 levels in HEK293 cells, an effect blocked by the PC inhibitor alpha1-PDX.","method":"Transient overexpression in HEK293 cells, ELISA/Western blot for APPalpha and Abeta40/42, alpha1-PDX inhibition","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based gain-of-function with inhibitor validation, single lab","pmids":["10537065"],"is_preprint":false},{"year":1999,"finding":"PC7 is colocalized with NGF in Schwann cells, macrophages, and perivascular smooth muscle cells of the injured sciatic nerve, and furin/PC7 mRNA levels increase after nerve lesion, suggesting roles in pro-NGF processing at the injury site.","method":"Northern blot, Western blot, immunocytochemistry, in situ hybridization on nerve explants","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 3 — colocalization evidence with expression data; no direct cleavage assay in this study","pmids":["9888313"],"is_preprint":false},{"year":2000,"finding":"PC7 does not process integrin alpha subunits (pro-alpha5, alpha6, alphav) in vitro or in LoVo cells, despite similar cleavage-site primary sequences, suggesting that substrate conformation (not just sequence) governs PC7-substrate interactions.","method":"In vitro cleavage assays, overexpression in furin-deficient LoVo cells, Western blot","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro and ex vivo assays clearly establishing lack of PC7 activity on integrin substrates","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 inhibitory potency arises from this folded structure involving charged (E8-R11-E15) and hydrophobic (W12, L19) side-chain interactions.","method":"Enzymatic inhibition assays, NMR structure determination with NOE restraints","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure combined with Ki measurement, mechanism directly mapped to specific residues","pmids":["10715106"],"is_preprint":false},{"year":2003,"finding":"PC7, along with furin and PC5, cleaves proVEGF-C at the dibasic motif HSIIRR227SL to generate mature VEGF-C; cleavage by these convertases promotes angiogenesis and lymphangiogenesis in vivo.","method":"Cotransfection in furin-deficient LoVo cells, in vitro fluorogenic peptide cleavage, subcutaneous injection into nude mice","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 — in vitro cleavage assay, cell-based rescue, and in vivo tumor model; replicated across multiple PCs","pmids":["12782675"],"is_preprint":false},{"year":2008,"finding":"PC7 (along with furin, PACE4, and PC5) cleaves the prohepcidin precursor at the RRRRR59DT site to generate biologically active hepcidin peptides; site-directed mutagenesis confirmed the cleavage site, and LoVo cell rescue experiments identified the active convertases.","method":"Cell transfection, LoVo cell complementation, site-directed mutagenesis, in vitro synthetic peptide cleavage","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of cleavage site plus in vitro and cell-based assays","pmids":["18664504"],"is_preprint":false},{"year":2009,"finding":"PC7 selectively cleaves the S1 site of pro-BMP4 in a developmentally regulated fashion in Xenopus embryos, distinct from furin/PC6 which cleave both S1 and S2 sites; this was established using site-selective inhibitor (alpha1-PDX variant) and antisense-mediated knockdown.","method":"Antisense gene knockdown in Xenopus oocytes/embryos, PC7-selective alpha1-PDX inhibitor variant, Western blot for BMP4 processing","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — pharmacological and genetic loss-of-function with site-specific resolution in a vertebrate model","pmids":["19651771"],"is_preprint":false},{"year":2010,"finding":"PC7 undergoes a unique zymogen activation in which the prosegment is primarily secreted alone as a non-inhibitory protein via the conventional Golgi-dependent pathway, while a fraction of mature PC7 reaches the cell surface via a brefeldin A- and COPII-independent unconventional secretory pathway regulated by its transmembrane domain. Two cysteines (Cys699 and Cys704) in the cytosolic tail are palmitoylated but this modification does not affect trafficking pathway choice.","method":"Brefeldin A treatment, COPII inhibition, domain-swap mutants between PC7 and furin TMCT, electron microscopy, palmitoylation assays, sulfation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (pharmacological inhibitors, domain swaps, EM, biochemical modifications), single lab","pmids":["21075846"],"is_preprint":false},{"year":2010,"finding":"PC7 is required for a second quality control checkpoint that rescues unstable MHC class I complexes after the peptide-loading complex (PLC) fails; PC7 knockdown in PLC-malfunctioning cells causes reduced MHC I surface levels and routes MHC I to lysosomes for degradation. PC7 can also directly liberate MHC I epitopes from peptide precursors. Furin is dispensable for this function.","method":"siRNA silencing of PC7, flow cytometry for MHC I surface levels, mass spectrometry of presented peptides, exogenous peptide precursor assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype plus mass spectrometry, single lab","pmids":["20164418"],"is_preprint":false},{"year":2011,"finding":"PC7 enhances EGF receptor pathway activation by processing the membrane-bound EGF precursor (pro-EGF) into an ~115-kDa transmembrane form (EGF-115) at an unusual VHPR290↓A motif; site-directed mutagenesis showed Arg290 is not critical, implicating indirect cleavage via PC7-activated latent serine and/or cysteine protease(s). EGF-115 shows stronger EGFR activation (elevated phospho-ERK1/2).","method":"Co-expression, site-directed mutagenesis, protease inhibitor profiling, ERK1/2 phosphorylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis combined with functional EGFR signaling readout; mechanism (indirect cleavage) defined by inhibitor panel","pmids":["21209099"],"is_preprint":false},{"year":2012,"finding":"PC7 is internalized from the plasma membrane via clathrin-coated vesicles; internalization requires a novel motif in the cytoplasmic tail between Ala713 and Cys726, with Pro, Leu, and Cys identified as essential residues by alanine scanning mutagenesis.","method":"Hypertonic inhibition, Pitstop 2 inhibitor, clathrin-coated vesicle isolation, antibody uptake assays, surface biotinylation, alanine scanning mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods identifying internalization motif; residue-level mutagenesis","pmids":["22294700"],"is_preprint":false},{"year":2013,"finding":"PC7 processes proBDNF into mature BDNF; in PC7 KO mice, mature BDNF protein levels are reduced in hippocampus and amygdala. PC7 KO mice exhibit severely impaired episodic and emotional memory that is rescued by the TrkB agonist 7,8-dihydroxyflavone.","method":"PC7 knockout mice, co-expression in COS-1 cells, primary hepatocyte culture, Western blot for BDNF, behavioral testing, pharmacological rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined cognitive phenotype, mechanistic rescue, and ex vivo processing data; multiple methods","pmids":["24101515"],"is_preprint":false},{"year":2013,"finding":"PCSK7 is essential for zebrafish development; morpholino-mediated PCSK7 knockdown causes defects in brain, eye, and otic vesicle leading to mortality within 7 days. PCSK7 contributes to mRNA expression and proteolytic cleavage of TGFβ1a; tgfβ1a morphants phenocopy pcsk7 morphants.","method":"Morpholino knockdown in zebrafish, genome-wide gene expression analysis, TGFβ1a cleavage assays, phenotypic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — in vivo KD with defined developmental phenotype and substrate identification; genetic epistasis (tgfb1a morphant phenocopy)","pmids":["24178295"],"is_preprint":false},{"year":2015,"finding":"PC7, along with furin and Pace4, regulates E-cadherin processing to control cell-cell adhesion during morula compaction and inner cell mass formation in mouse blastocysts; live imaging of a transgenic reporter substrate showed PC7 activity in inner and outer cells in partially non-overlapping compartments.","method":"PC mutant mouse embryos, live imaging with transgenic fluorescent reporter substrate, E-cadherin processing assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — live imaging biosensor in vivo plus genetic mutant embryos; direct causal link to E-cadherin cleavage","pmids":["26416966"],"is_preprint":false},{"year":2018,"finding":"Endogenous PC7, unlike overexpressed PC7, is active in distinct vesicles separable from Furin-active endosomes. A PLC motif in the cytosolic tail of PC7 is dispensable for endosomal activity but required for TGN recycling and to rescue proActivin-A cleavage in Furin-depleted cells. PC7 cleaves Notch1 independently of PLC-mediated TGN access.","method":"Compartment-targeted biosensors, inhibitor profiling, PLC motif mutagenesis, substrate complementation assays in Furin-depleted B16F1 cells","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — novel biosensor technology, mutagenesis, substrate rescue; multiple orthogonal approaches","pmids":["29466742"],"is_preprint":false},{"year":2019,"finding":"In HepG2 cells, PCSK7 deletion reduces lipogenesis, fat accumulation, inflammation, TGF-β pathway activation, and fibrogenesis; hepatic PCSK7 expression correlates with lipogenic gene expression.","method":"CRISPR/siRNA deletion in HepG2 cells, transcriptomic analysis, lipid accumulation assays","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based KO with multiple functional readouts; single lab","pmids":["30918065"],"is_preprint":false},{"year":2020,"finding":"PC7 binds to and enhances lysosomal degradation of apoA-V in a nonenzymatic fashion; ER-retained forms of PC7 also degrade apoA-V via an ER-lysosomal communication inhibited by bafilomycin A1. The R504H natural variant enhances Ser505 phosphorylation by secretory kinase Fam20C; phosphomimetic PC7-S505E shows reduced apoA-V degradation. In Pcsk7-/- mice, plasma apoA-V and adipocyte LpL activity are increased.","method":"Co-expression and co-IP in HuH7 cells, bafilomycin A1/chloroquine/NH4Cl treatment, Pcsk7-/- mouse studies, in vitro kinase assay with Fam20C","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 — biochemical binding/degradation assays, pharmacological inhibitors, phosphorylation mechanism defined, KO mouse validation; multiple orthogonal methods","pmids":["31945259"],"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; shedding of CASC4 disrupts its anti-migratory role and generates a membrane-bound N-terminal fragment that promotes podosome-like structures, increased cellular migration and invasion.","method":"Quantitative N-glycoproteomics screen, site-directed mutagenesis, siRNA silencing, migration/invasion assays, paxillin focal adhesion staining, compartment-specific activity assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — proteomics substrate discovery, mutagenesis of cleavage site, cell functional assays; multiple methods","pmids":["32820145"],"is_preprint":false},{"year":2020,"finding":"A novel EXEXXXL725 motif in the cytosolic tail of PC7 is critical for its endosomal activity on human transferrin receptor 1 (hTfR1): Glu-719, Glu-721, and Leu-725 are essential for hTfR1 shedding; Leu-725 specifically enhances PC7 localization to early endosomes; the motif is recognized by adaptor protein 2 (AP-2). Deletion of the transmembrane-cytosolic tail abolishes hTfR1 shedding.","method":"CT deletion and alanine mutagenesis, NMR of 14-mer peptides, immunocytochemistry, AP-2 co-IP, hTfR1 shedding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — NMR structure, mutagenesis at residue level, binding partner identification, functional shedding assay; multiple orthogonal methods","pmids":["31915245"],"is_preprint":false},{"year":2022,"finding":"miR-125a-5p, miR-143-3p, and miR-409-3p directly bind the 3'-UTR of PCSK7 mRNA and reduce PC7 expression; overexpression of miR-125a-5p in Huh7 cells inhibits PC7 protein expression and its ability to cleave human transferrin receptor 1.","method":"Dual-luciferase reporter assay, qPCR, Western blot, transferrin receptor 1 cleavage assay","journal":"Metabolites","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase validates direct 3'-UTR binding, functional substrate cleavage assay; single lab","pmids":["35888711"],"is_preprint":false},{"year":2023,"finding":"Independent of its proteolytic activity, membrane-bound PCSK7 binds apoB100 in the ER and enhances its secretion; loss of PCSK7/Pcsk7 leads to apoB100 degradation via ubiquitin-proteasome pathway, triggering UPR, autophagy, and β-oxidation, reducing hepatic lipid accumulation. In Pcsk7-/- mice after NAFLD diet, liver recovery is improved. GalNAc-ASO hepatocyte-targeted knockdown of Pcsk7 recapitulates these results.","method":"Co-expression, Co-IP in hepatic cell lines, Pcsk7-/- mouse NAFLD model, GalNAc-ASO knockdown, proteasome inhibition, autophagy assays","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 2 — binding demonstrated biochemically, KO mouse with dietary phenotype, ASO validation, mechanistic cascade defined; multiple orthogonal methods across in vitro and in vivo","pmids":["37967646"],"is_preprint":false}],"current_model":"PCSK7 encodes PC7, the most ancient membrane-bound subtilisin/kexin-type serine protease that cleaves precursor proteins (including proBDNF, proVEGF-C, prohepcidin, gp160, CASC4, TGFβ1a, E-cadherin) at basic residue motifs primarily in the trans-Golgi network and endosomes; it also acts non-enzymatically in the ER to bind apoB100 and promote its secretion, and non-enzymatically degrades apoA-V via an ER-lysosomal pathway regulated by Fam20C-mediated Ser505 phosphorylation, with endosomal trafficking and substrate access governed by a novel EXEXXXL cytosolic tail motif recognized by AP-2."},"narrative":{"teleology":[{"year":1996,"claim":"Identification of PC7 as a new member of the proprotein convertase family established that mammals possess a seventh membrane-bound subtilisin/kexin protease, phylogenetically closest to yeast kexin and the most divergent mammalian convertase.","evidence":"cDNA cloning, Northern blot, in situ hybridization, and linkage analysis of human and mouse PCSK7","pmids":["8622945"],"confidence":"High","gaps":["No enzymatic activity demonstrated in original cloning paper","Substrate repertoire unknown","Subcellular site of action undefined"]},{"year":1997,"claim":"Biochemical characterization revealed that PC7 is a calcium-dependent serine protease with furin-like pH optimum, resolving whether the newly cloned gene encoded an active enzyme and defining its basic enzymology.","evidence":"Vaccinia virus overexpression in BSC40 cells with fluorogenic substrates and in vitro peptide cleavage; also shown to cleave HIV gp160 in cell-based assays","pmids":["9242622","9094426"],"confidence":"High","gaps":["Endogenous substrates not yet identified","Substrate selectivity rules not defined"]},{"year":1999,"claim":"Demonstration that the PC7 prosegment acts as a potent autoinhibitor (Ki ~7 nM for C-terminal peptide) and that its helical structure dictates inhibitory potency provided the first mechanistic understanding of PC7 zymogen activation and potential therapeutic inhibition strategies.","evidence":"Recombinant prosegment inhibition assays, NMR structure of inhibitory peptide, ex vivo blockade of proNGF/proBDNF processing","pmids":["10567353","10715106"],"confidence":"High","gaps":["Full-length structure of mature PC7 unavailable","Physiological timing of prosegment release not defined"]},{"year":2003,"claim":"Identification of proVEGF-C and prohepcidin as PC7 substrates expanded PC7's physiological role beyond neurotrophins to angiogenesis/lymphangiogenesis and iron homeostasis.","evidence":"LoVo cell complementation, in vitro cleavage, and in vivo tumor model (VEGF-C); mutagenesis plus cell-based assays (hepcidin)","pmids":["12782675","18664504"],"confidence":"High","gaps":["Relative contribution of PC7 versus furin/PACE4 on these substrates in vivo unclear","No PC7-selective inhibitor used"]},{"year":2009,"claim":"Demonstration of PC7's selective cleavage of the S1 site of pro-BMP4 during Xenopus embryogenesis established that PC7 has substrate-site selectivity distinct from furin/PC6, with developmental consequences.","evidence":"Antisense knockdown and PC7-selective α1-PDX inhibitor variant in Xenopus embryos","pmids":["19651771"],"confidence":"High","gaps":["Mammalian in vivo validation of BMP4 processing by PC7 not shown","Structural basis for S1 selectivity unresolved"]},{"year":2010,"claim":"Discovery that mature PC7 reaches the cell surface via a COPII-independent unconventional secretory route—controlled by its transmembrane domain and accompanied by secretion of a non-inhibitory prosegment—revealed a trafficking mechanism unique among proprotein convertases.","evidence":"Brefeldin A treatment, COPII inhibition, TM-domain swaps, palmitoylation assays, electron microscopy in HEK293 cells","pmids":["21075846"],"confidence":"High","gaps":["Identity of the unconventional trafficking machinery unknown","Whether palmitoylation of Cys699/Cys704 regulates other functions unaddressed"]},{"year":2010,"claim":"PC7 was shown to function in MHC class I antigen presentation by rescuing unstable peptide–MHC I complexes when the peptide-loading complex fails, establishing a non-redundant immune role for PC7 distinct from furin.","evidence":"siRNA silencing of PC7 in PLC-deficient human cells, flow cytometry, mass spectrometry of presented peptides","pmids":["20164418"],"confidence":"High","gaps":["Direct MHC I peptide trimming substrate specificity not defined","In vivo immune consequences of PC7 loss not tested"]},{"year":2013,"claim":"PC7 knockout mice demonstrated that PC7 is the physiologically relevant convertase for proBDNF maturation in hippocampus and amygdala, with loss causing severe memory deficits rescuable by a TrkB agonist—providing causal in vivo evidence for PC7's neurotrophin-processing role.","evidence":"Pcsk7−/− mice, Western blot for BDNF in brain regions, behavioral testing, pharmacological rescue with 7,8-DHF","pmids":["24101515"],"confidence":"High","gaps":["Whether PC7 loss affects other neurotrophins in vivo not examined","Human genetic evidence linking PCSK7 to memory disorders lacking"]},{"year":2013,"claim":"Zebrafish pcsk7 knockdown causing brain, eye, and otic vesicle defects—phenocopied by tgfβ1a morphants—established TGFβ1a as a developmental substrate and confirmed PC7's essential role in vertebrate organogenesis.","evidence":"Morpholino knockdown in zebrafish, transcriptomics, TGFβ1a cleavage assays, epistasis analysis","pmids":["24178295"],"confidence":"High","gaps":["Morpholino off-target effects possible; genetic mutant confirmation pending","Whether PC7 acts cell-autonomously during development not resolved"]},{"year":2015,"claim":"Live imaging of PC7 activity during mouse preimplantation development showed that PC7, furin, and Pace4 regulate E-cadherin processing to control compaction and inner cell mass formation, demonstrating compartmentalized convertase activity in vivo.","evidence":"PC mutant mouse embryos with transgenic fluorescent reporter substrate, live imaging, E-cadherin processing assays","pmids":["26416966"],"confidence":"High","gaps":["Relative quantitative contribution of each convertase to E-cadherin cleavage not resolved","Downstream signaling consequences of E-cadherin fragments uncharacterized"]},{"year":2018,"claim":"Compartment-resolved biosensor imaging showed that endogenous PC7 is active in vesicles distinct from furin-active endosomes, and that a cytosolic PLC motif controls TGN recycling but is dispensable for endosomal activity—redefining the spatial logic of PC7 versus furin substrate access.","evidence":"Compartment-targeted biosensors, PLC motif mutagenesis, substrate rescue in furin-depleted B16F1 cells","pmids":["29466742"],"confidence":"High","gaps":["Identity of PC7-positive endosomal compartment at the molecular level undefined","How PC7 and furin are sorted into distinct vesicles unknown"]},{"year":2020,"claim":"Multiple studies resolved key non-enzymatic and enzymatic functions: PC7 degrades apoA-V non-enzymatically via an ER–lysosome pathway modulated by Fam20C phosphorylation at Ser505; PC7 sheds CASC4 at KR66 in endosomes/TGN to promote migration; and the EXEXXXL motif in the cytosolic tail—recognized by AP-2—governs endosomal localization and hTfR1 shedding.","evidence":"Co-IP, bafilomycin/chloroquine treatment, Pcsk7−/− mice, Fam20C kinase assays (apoA-V); N-glycoproteomics, mutagenesis, migration assays (CASC4); NMR of CT peptides, AP-2 co-IP, alanine scanning (EXEXXXL/AP-2)","pmids":["31945259","32820145","31915245"],"confidence":"High","gaps":["Structural basis for AP-2 recognition of the EXEXXXL motif not determined","Whether Fam20C-mediated phosphorylation regulates enzymatic activity on other substrates unknown","In vivo relevance of CASC4 shedding to cancer progression not demonstrated"]},{"year":2023,"claim":"PC7 was shown to bind apoB100 in the ER independently of its catalytic activity and promote VLDL secretion; loss of PC7 diverts apoB100 to proteasomal degradation, triggering UPR, autophagy, and β-oxidation that reduce hepatic lipid accumulation and improve NAFLD outcomes in mice.","evidence":"Co-IP in hepatic cells, Pcsk7−/− mouse NAFLD model, GalNAc-ASO hepatocyte knockdown, proteasome inhibition, autophagy assays","pmids":["37967646"],"confidence":"High","gaps":["Structural determinants of the PC7–apoB100 interaction undefined","Whether the non-enzymatic ER function is conserved for other secretory cargo unknown","Human genetic validation of PCSK7 as a NAFLD modifier lacking"]},{"year":null,"claim":"No full-length structure of PC7 exists, the identity of the unconventional secretory pathway carrier is unknown, and the in vivo hierarchy among enzymatic and non-enzymatic functions in specific tissues remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of PC7","Unconventional secretory route machinery unidentified","Tissue-specific conditional knockouts needed to dissect enzymatic versus non-enzymatic roles"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,8,9,10,15,16,17,21]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,3,7]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11,18,21]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[18,22]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,14,22]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,20,24]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[18,22]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3,8,9,15,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,13,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,16,17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[19,20,24]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[11,14,22]}],"complexes":[],"partners":["BDNF","APOB","APOA5","CASC4","TFRC","AP2A1","FAM20C","VEGFC"],"other_free_text":[]},"mechanistic_narrative":"PCSK7 encodes proprotein convertase 7 (PC7), the most evolutionarily divergent membrane-bound subtilisin/kexin-type serine protease, which cleaves diverse precursor proteins at basic-residue motifs primarily in the trans-Golgi network and endosomes to regulate neurotrophin maturation, growth factor signaling, immune peptide loading, and cell adhesion [PMID:8622945, PMID:9242622, PMID:24101515, PMID:26416966, PMID:20164418]. Established enzymatic substrates include proBDNF, proVEGF-C, prohepcidin, pro-BMP4, TGFβ1a, CASC4, and HIV gp160, with substrate selectivity governed by conformation rather than primary sequence alone [PMID:24101515, PMID:12782675, PMID:18664504, PMID:19651771, PMID:24178295, PMID:32820145, PMID:10657249]. PC7 also functions non-enzymatically: it binds apoB100 in the ER to promote VLDL secretion, and targets apoA-V for lysosomal degradation through an ER–lysosome pathway regulated by Fam20C-mediated Ser505 phosphorylation [PMID:37967646, PMID:31945259]. Endosomal trafficking and substrate access depend on a cytosolic-tail EXEXXXL motif recognized by AP-2, while PC7 reaches the cell surface via a COPII-independent unconventional secretory route governed by its transmembrane domain [PMID:31915245, PMID:21075846]."},"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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rostratum LPC-001.","date":"2018","source":"Journal of Asian natural products research","url":"https://pubmed.ncbi.nlm.nih.gov/30595053","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 bio","url":"https://pubmed.ncbi.nlm.nih.gov/25349778","citation_count":10,"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":"84712","id":"PMC_84712","title":"Studies with murine LPC-1 plasmacytoma using [6-14C]arginine.","date":"1979","source":"Cell and tissue 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activation.","date":"2000","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/11024163","citation_count":9,"is_preprint":false},{"pmid":"33565643","id":"PMC_33565643","title":"Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis.","date":"2021","source":"Alimentary pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/33565643","citation_count":8,"is_preprint":false},{"pmid":"31915245","id":"PMC_31915245","title":"The motif EXEXXXL in the cytosolic tail of the secretory human proprotein convertase PC7 regulates its trafficking and cleavage activity.","date":"2020","source":"The Journal of biological 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":"31025599","id":"PMC_31025599","title":"Agonism activities of lyso-phosphatidylcholines (LPC) Ligands binding to peroxisome proliferator-activated receptor gamma (PPARγ).","date":"2019","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/31025599","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 research","url":"https://pubmed.ncbi.nlm.nih.gov/445451","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 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747-amino acid mature form; phylogenetic analysis placed it as the most divergent mammalian convertase and closest to yeast kexin.\",\n      \"method\": \"cDNA cloning, Northern blot, in situ hybridization, linkage analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning and structural characterization with multiple orthogonal methods; foundational paper with 221 citations\",\n      \"pmids\": [\"8622945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Rat PC7 is synthesized as a glycosylated zymogen (101 kDa) processed to mature PC7 (89 kDa) in the ER; it has enzymatic activity on fluorogenic peptidyl substrates with pH optimum and Ca2+ dependence similar to furin, correctly processes pro-PTH and pro-PC4 peptides, but not pro-EGF peptide.\",\n      \"method\": \"Vaccinia virus overexpression in BSC40 cells, enzymatic activity assays with fluorogenic substrates, in vitro peptide cleavage assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic characterization with multiple substrates; first biochemical description of PC7 activity\",\n      \"pmids\": [\"9242622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PC7 can cleave HIV envelope glycoprotein gp160 into gp120/gp41 in a cell-type-specific manner, similar to furin, and is expressed at higher levels in activated T4 lymphocytes; demonstrated using cell-based co-expression assays and in vitro cleavage of synthetic peptides.\",\n      \"method\": \"RT-PCR, cell-based co-expression assay in BSC40 and AtT20 cells, in vitro synthetic peptide cleavage\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based and in vitro assays, single lab\",\n      \"pmids\": [\"9094426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The prosegment of PC7 acts as a potent inhibitor of PC7 enzyme activity; recombinant bacterial prosegments inhibit PC7 in vitro and, when expressed via vaccinia virus ex vivo, inhibit processing of NGF and BDNF precursors in trans.\",\n      \"method\": \"Recombinant prosegment purification, in vitro fluorogenic peptide assays, ex vivo vaccinia virus expression, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro inhibition assays combined with ex vivo functional validation\",\n      \"pmids\": [\"10567353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PC7 contributes to the alpha-secretase pathway for beta-amyloid precursor protein (betaAPP): overexpression of PC7 increases APPalpha secretion and reduces Abeta40/42 levels in HEK293 cells, an effect blocked by the PC inhibitor alpha1-PDX.\",\n      \"method\": \"Transient overexpression in HEK293 cells, ELISA/Western blot for APPalpha and Abeta40/42, alpha1-PDX inhibition\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based gain-of-function with inhibitor validation, single lab\",\n      \"pmids\": [\"10537065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PC7 is colocalized with NGF in Schwann cells, macrophages, and perivascular smooth muscle cells of the injured sciatic nerve, and furin/PC7 mRNA levels increase after nerve lesion, suggesting roles in pro-NGF processing at the injury site.\",\n      \"method\": \"Northern blot, Western blot, immunocytochemistry, in situ hybridization on nerve explants\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — colocalization evidence with expression data; no direct cleavage assay in this study\",\n      \"pmids\": [\"9888313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PC7 does not process integrin alpha subunits (pro-alpha5, alpha6, alphav) in vitro or in LoVo cells, despite similar cleavage-site primary sequences, suggesting that substrate conformation (not just sequence) governs PC7-substrate interactions.\",\n      \"method\": \"In vitro cleavage assays, overexpression in furin-deficient LoVo cells, Western blot\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro and ex vivo assays clearly establishing lack of PC7 activity on integrin substrates\",\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 inhibitory potency arises from this folded structure involving charged (E8-R11-E15) and hydrophobic (W12, L19) side-chain interactions.\",\n      \"method\": \"Enzymatic inhibition assays, NMR structure determination with NOE restraints\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure combined with Ki measurement, mechanism directly mapped to specific residues\",\n      \"pmids\": [\"10715106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PC7, along with furin and PC5, cleaves proVEGF-C at the dibasic motif HSIIRR227SL to generate mature VEGF-C; cleavage by these convertases promotes angiogenesis and lymphangiogenesis in vivo.\",\n      \"method\": \"Cotransfection in furin-deficient LoVo cells, in vitro fluorogenic peptide cleavage, subcutaneous injection into nude mice\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro cleavage assay, cell-based rescue, and in vivo tumor model; replicated across multiple PCs\",\n      \"pmids\": [\"12782675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PC7 (along with furin, PACE4, and PC5) cleaves the prohepcidin precursor at the RRRRR59DT site to generate biologically active hepcidin peptides; site-directed mutagenesis confirmed the cleavage site, and LoVo cell rescue experiments identified the active convertases.\",\n      \"method\": \"Cell transfection, LoVo cell complementation, site-directed mutagenesis, in vitro synthetic peptide cleavage\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of cleavage site plus in vitro and cell-based assays\",\n      \"pmids\": [\"18664504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PC7 selectively cleaves the S1 site of pro-BMP4 in a developmentally regulated fashion in Xenopus embryos, distinct from furin/PC6 which cleave both S1 and S2 sites; this was established using site-selective inhibitor (alpha1-PDX variant) and antisense-mediated knockdown.\",\n      \"method\": \"Antisense gene knockdown in Xenopus oocytes/embryos, PC7-selective alpha1-PDX inhibitor variant, Western blot for BMP4 processing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — pharmacological and genetic loss-of-function with site-specific resolution in a vertebrate model\",\n      \"pmids\": [\"19651771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PC7 undergoes a unique zymogen activation in which the prosegment is primarily secreted alone as a non-inhibitory protein via the conventional Golgi-dependent pathway, while a fraction of mature PC7 reaches the cell surface via a brefeldin A- and COPII-independent unconventional secretory pathway regulated by its transmembrane domain. Two cysteines (Cys699 and Cys704) in the cytosolic tail are palmitoylated but this modification does not affect trafficking pathway choice.\",\n      \"method\": \"Brefeldin A treatment, COPII inhibition, domain-swap mutants between PC7 and furin TMCT, electron microscopy, palmitoylation assays, sulfation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pharmacological inhibitors, domain swaps, EM, biochemical modifications), single lab\",\n      \"pmids\": [\"21075846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PC7 is required for a second quality control checkpoint that rescues unstable MHC class I complexes after the peptide-loading complex (PLC) fails; PC7 knockdown in PLC-malfunctioning cells causes reduced MHC I surface levels and routes MHC I to lysosomes for degradation. PC7 can also directly liberate MHC I epitopes from peptide precursors. Furin is dispensable for this function.\",\n      \"method\": \"siRNA silencing of PC7, flow cytometry for MHC I surface levels, mass spectrometry of presented peptides, exogenous peptide precursor assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype plus mass spectrometry, single lab\",\n      \"pmids\": [\"20164418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PC7 enhances EGF receptor pathway activation by processing the membrane-bound EGF precursor (pro-EGF) into an ~115-kDa transmembrane form (EGF-115) at an unusual VHPR290↓A motif; site-directed mutagenesis showed Arg290 is not critical, implicating indirect cleavage via PC7-activated latent serine and/or cysteine protease(s). EGF-115 shows stronger EGFR activation (elevated phospho-ERK1/2).\",\n      \"method\": \"Co-expression, site-directed mutagenesis, protease inhibitor profiling, ERK1/2 phosphorylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis combined with functional EGFR signaling readout; mechanism (indirect cleavage) defined by inhibitor panel\",\n      \"pmids\": [\"21209099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PC7 is internalized from the plasma membrane via clathrin-coated vesicles; internalization requires a novel motif in the cytoplasmic tail between Ala713 and Cys726, with Pro, Leu, and Cys identified as essential residues by alanine scanning mutagenesis.\",\n      \"method\": \"Hypertonic inhibition, Pitstop 2 inhibitor, clathrin-coated vesicle isolation, antibody uptake assays, surface biotinylation, alanine scanning mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods identifying internalization motif; residue-level mutagenesis\",\n      \"pmids\": [\"22294700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PC7 processes proBDNF into mature BDNF; in PC7 KO mice, mature BDNF protein levels are reduced in hippocampus and amygdala. PC7 KO mice exhibit severely impaired episodic and emotional memory that is rescued by the TrkB agonist 7,8-dihydroxyflavone.\",\n      \"method\": \"PC7 knockout mice, co-expression in COS-1 cells, primary hepatocyte culture, Western blot for BDNF, behavioral testing, pharmacological rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cognitive phenotype, mechanistic rescue, and ex vivo processing data; multiple methods\",\n      \"pmids\": [\"24101515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PCSK7 is essential for zebrafish development; morpholino-mediated PCSK7 knockdown causes defects in brain, eye, and otic vesicle leading to mortality within 7 days. PCSK7 contributes to mRNA expression and proteolytic cleavage of TGFβ1a; tgfβ1a morphants phenocopy pcsk7 morphants.\",\n      \"method\": \"Morpholino knockdown in zebrafish, genome-wide gene expression analysis, TGFβ1a cleavage assays, phenotypic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD with defined developmental phenotype and substrate identification; genetic epistasis (tgfb1a morphant phenocopy)\",\n      \"pmids\": [\"24178295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PC7, along with furin and Pace4, regulates E-cadherin processing to control cell-cell adhesion during morula compaction and inner cell mass formation in mouse blastocysts; live imaging of a transgenic reporter substrate showed PC7 activity in inner and outer cells in partially non-overlapping compartments.\",\n      \"method\": \"PC mutant mouse embryos, live imaging with transgenic fluorescent reporter substrate, E-cadherin processing assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — live imaging biosensor in vivo plus genetic mutant embryos; direct causal link to E-cadherin cleavage\",\n      \"pmids\": [\"26416966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Endogenous PC7, unlike overexpressed PC7, is active in distinct vesicles separable from Furin-active endosomes. A PLC motif in the cytosolic tail of PC7 is dispensable for endosomal activity but required for TGN recycling and to rescue proActivin-A cleavage in Furin-depleted cells. PC7 cleaves Notch1 independently of PLC-mediated TGN access.\",\n      \"method\": \"Compartment-targeted biosensors, inhibitor profiling, PLC motif mutagenesis, substrate complementation assays in Furin-depleted B16F1 cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — novel biosensor technology, mutagenesis, substrate rescue; multiple orthogonal approaches\",\n      \"pmids\": [\"29466742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In HepG2 cells, PCSK7 deletion reduces lipogenesis, fat accumulation, inflammation, TGF-β pathway activation, and fibrogenesis; hepatic PCSK7 expression correlates with lipogenic gene expression.\",\n      \"method\": \"CRISPR/siRNA deletion in HepG2 cells, transcriptomic analysis, lipid accumulation assays\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based KO with multiple functional readouts; single lab\",\n      \"pmids\": [\"30918065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PC7 binds to and enhances lysosomal degradation of apoA-V in a nonenzymatic fashion; ER-retained forms of PC7 also degrade apoA-V via an ER-lysosomal communication inhibited by bafilomycin A1. The R504H natural variant enhances Ser505 phosphorylation by secretory kinase Fam20C; phosphomimetic PC7-S505E shows reduced apoA-V degradation. In Pcsk7-/- mice, plasma apoA-V and adipocyte LpL activity are increased.\",\n      \"method\": \"Co-expression and co-IP in HuH7 cells, bafilomycin A1/chloroquine/NH4Cl treatment, Pcsk7-/- mouse studies, in vitro kinase assay with Fam20C\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical binding/degradation assays, pharmacological inhibitors, phosphorylation mechanism defined, KO mouse validation; multiple orthogonal methods\",\n      \"pmids\": [\"31945259\"],\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; shedding of CASC4 disrupts its anti-migratory role and generates a membrane-bound N-terminal fragment that promotes podosome-like structures, increased cellular migration and invasion.\",\n      \"method\": \"Quantitative N-glycoproteomics screen, site-directed mutagenesis, siRNA silencing, migration/invasion assays, paxillin focal adhesion staining, compartment-specific activity assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomics substrate discovery, mutagenesis of cleavage site, cell functional assays; multiple methods\",\n      \"pmids\": [\"32820145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A novel EXEXXXL725 motif in the cytosolic tail of PC7 is critical for its endosomal activity on human transferrin receptor 1 (hTfR1): Glu-719, Glu-721, and Leu-725 are essential for hTfR1 shedding; Leu-725 specifically enhances PC7 localization to early endosomes; the motif is recognized by adaptor protein 2 (AP-2). Deletion of the transmembrane-cytosolic tail abolishes hTfR1 shedding.\",\n      \"method\": \"CT deletion and alanine mutagenesis, NMR of 14-mer peptides, immunocytochemistry, AP-2 co-IP, hTfR1 shedding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — NMR structure, mutagenesis at residue level, binding partner identification, functional shedding assay; multiple orthogonal methods\",\n      \"pmids\": [\"31915245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-125a-5p, miR-143-3p, and miR-409-3p directly bind the 3'-UTR of PCSK7 mRNA and reduce PC7 expression; overexpression of miR-125a-5p in Huh7 cells inhibits PC7 protein expression and its ability to cleave human transferrin receptor 1.\",\n      \"method\": \"Dual-luciferase reporter assay, qPCR, Western blot, transferrin receptor 1 cleavage assay\",\n      \"journal\": \"Metabolites\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase validates direct 3'-UTR binding, functional substrate cleavage assay; single lab\",\n      \"pmids\": [\"35888711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Independent of its proteolytic activity, membrane-bound PCSK7 binds apoB100 in the ER and enhances its secretion; loss of PCSK7/Pcsk7 leads to apoB100 degradation via ubiquitin-proteasome pathway, triggering UPR, autophagy, and β-oxidation, reducing hepatic lipid accumulation. In Pcsk7-/- mice after NAFLD diet, liver recovery is improved. GalNAc-ASO hepatocyte-targeted knockdown of Pcsk7 recapitulates these results.\",\n      \"method\": \"Co-expression, Co-IP in hepatic cell lines, Pcsk7-/- mouse NAFLD model, GalNAc-ASO knockdown, proteasome inhibition, autophagy assays\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — binding demonstrated biochemically, KO mouse with dietary phenotype, ASO validation, mechanistic cascade defined; multiple orthogonal methods across in vitro and in vivo\",\n      \"pmids\": [\"37967646\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PCSK7 encodes PC7, the most ancient membrane-bound subtilisin/kexin-type serine protease that cleaves precursor proteins (including proBDNF, proVEGF-C, prohepcidin, gp160, CASC4, TGFβ1a, E-cadherin) at basic residue motifs primarily in the trans-Golgi network and endosomes; it also acts non-enzymatically in the ER to bind apoB100 and promote its secretion, and non-enzymatically degrades apoA-V via an ER-lysosomal pathway regulated by Fam20C-mediated Ser505 phosphorylation, with endosomal trafficking and substrate access governed by a novel EXEXXXL cytosolic tail motif recognized by AP-2.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PCSK7 encodes proprotein convertase 7 (PC7), the most evolutionarily divergent membrane-bound subtilisin/kexin-type serine protease, which cleaves diverse precursor proteins at basic-residue motifs primarily in the trans-Golgi network and endosomes to regulate neurotrophin maturation, growth factor signaling, immune peptide loading, and cell adhesion [PMID:8622945, PMID:9242622, PMID:24101515, PMID:26416966, PMID:20164418]. Established enzymatic substrates include proBDNF, proVEGF-C, prohepcidin, pro-BMP4, TGFβ1a, CASC4, and HIV gp160, with substrate selectivity governed by conformation rather than primary sequence alone [PMID:24101515, PMID:12782675, PMID:18664504, PMID:19651771, PMID:24178295, PMID:32820145, PMID:10657249]. PC7 also functions non-enzymatically: it binds apoB100 in the ER to promote VLDL secretion, and targets apoA-V for lysosomal degradation through an ER–lysosome pathway regulated by Fam20C-mediated Ser505 phosphorylation [PMID:37967646, PMID:31945259]. Endosomal trafficking and substrate access depend on a cytosolic-tail EXEXXXL motif recognized by AP-2, while PC7 reaches the cell surface via a COPII-independent unconventional secretory route governed by its transmembrane domain [PMID:31915245, PMID:21075846].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of PC7 as a new member of the proprotein convertase family established that mammals possess a seventh membrane-bound subtilisin/kexin protease, phylogenetically closest to yeast kexin and the most divergent mammalian convertase.\",\n      \"evidence\": \"cDNA cloning, Northern blot, in situ hybridization, and linkage analysis of human and mouse PCSK7\",\n      \"pmids\": [\"8622945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No enzymatic activity demonstrated in original cloning paper\", \"Substrate repertoire unknown\", \"Subcellular site of action undefined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Biochemical characterization revealed that PC7 is a calcium-dependent serine protease with furin-like pH optimum, resolving whether the newly cloned gene encoded an active enzyme and defining its basic enzymology.\",\n      \"evidence\": \"Vaccinia virus overexpression in BSC40 cells with fluorogenic substrates and in vitro peptide cleavage; also shown to cleave HIV gp160 in cell-based assays\",\n      \"pmids\": [\"9242622\", \"9094426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous substrates not yet identified\", \"Substrate selectivity rules not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstration that the PC7 prosegment acts as a potent autoinhibitor (Ki ~7 nM for C-terminal peptide) and that its helical structure dictates inhibitory potency provided the first mechanistic understanding of PC7 zymogen activation and potential therapeutic inhibition strategies.\",\n      \"evidence\": \"Recombinant prosegment inhibition assays, NMR structure of inhibitory peptide, ex vivo blockade of proNGF/proBDNF processing\",\n      \"pmids\": [\"10567353\", \"10715106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length structure of mature PC7 unavailable\", \"Physiological timing of prosegment release not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of proVEGF-C and prohepcidin as PC7 substrates expanded PC7's physiological role beyond neurotrophins to angiogenesis/lymphangiogenesis and iron homeostasis.\",\n      \"evidence\": \"LoVo cell complementation, in vitro cleavage, and in vivo tumor model (VEGF-C); mutagenesis plus cell-based assays (hepcidin)\",\n      \"pmids\": [\"12782675\", \"18664504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of PC7 versus furin/PACE4 on these substrates in vivo unclear\", \"No PC7-selective inhibitor used\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstration of PC7's selective cleavage of the S1 site of pro-BMP4 during Xenopus embryogenesis established that PC7 has substrate-site selectivity distinct from furin/PC6, with developmental consequences.\",\n      \"evidence\": \"Antisense knockdown and PC7-selective α1-PDX inhibitor variant in Xenopus embryos\",\n      \"pmids\": [\"19651771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian in vivo validation of BMP4 processing by PC7 not shown\", \"Structural basis for S1 selectivity unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that mature PC7 reaches the cell surface via a COPII-independent unconventional secretory route—controlled by its transmembrane domain and accompanied by secretion of a non-inhibitory prosegment—revealed a trafficking mechanism unique among proprotein convertases.\",\n      \"evidence\": \"Brefeldin A treatment, COPII inhibition, TM-domain swaps, palmitoylation assays, electron microscopy in HEK293 cells\",\n      \"pmids\": [\"21075846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the unconventional trafficking machinery unknown\", \"Whether palmitoylation of Cys699/Cys704 regulates other functions unaddressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"PC7 was shown to function in MHC class I antigen presentation by rescuing unstable peptide–MHC I complexes when the peptide-loading complex fails, establishing a non-redundant immune role for PC7 distinct from furin.\",\n      \"evidence\": \"siRNA silencing of PC7 in PLC-deficient human cells, flow cytometry, mass spectrometry of presented peptides\",\n      \"pmids\": [\"20164418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MHC I peptide trimming substrate specificity not defined\", \"In vivo immune consequences of PC7 loss not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"PC7 knockout mice demonstrated that PC7 is the physiologically relevant convertase for proBDNF maturation in hippocampus and amygdala, with loss causing severe memory deficits rescuable by a TrkB agonist—providing causal in vivo evidence for PC7's neurotrophin-processing role.\",\n      \"evidence\": \"Pcsk7−/− mice, Western blot for BDNF in brain regions, behavioral testing, pharmacological rescue with 7,8-DHF\",\n      \"pmids\": [\"24101515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PC7 loss affects other neurotrophins in vivo not examined\", \"Human genetic evidence linking PCSK7 to memory disorders lacking\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Zebrafish pcsk7 knockdown causing brain, eye, and otic vesicle defects—phenocopied by tgfβ1a morphants—established TGFβ1a as a developmental substrate and confirmed PC7's essential role in vertebrate organogenesis.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish, transcriptomics, TGFβ1a cleavage assays, epistasis analysis\",\n      \"pmids\": [\"24178295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Morpholino off-target effects possible; genetic mutant confirmation pending\", \"Whether PC7 acts cell-autonomously during development not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Live imaging of PC7 activity during mouse preimplantation development showed that PC7, furin, and Pace4 regulate E-cadherin processing to control compaction and inner cell mass formation, demonstrating compartmentalized convertase activity in vivo.\",\n      \"evidence\": \"PC mutant mouse embryos with transgenic fluorescent reporter substrate, live imaging, E-cadherin processing assays\",\n      \"pmids\": [\"26416966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative quantitative contribution of each convertase to E-cadherin cleavage not resolved\", \"Downstream signaling consequences of E-cadherin fragments uncharacterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Compartment-resolved biosensor imaging showed that endogenous PC7 is active in vesicles distinct from furin-active endosomes, and that a cytosolic PLC motif controls TGN recycling but is dispensable for endosomal activity—redefining the spatial logic of PC7 versus furin substrate access.\",\n      \"evidence\": \"Compartment-targeted biosensors, PLC motif mutagenesis, substrate rescue in furin-depleted B16F1 cells\",\n      \"pmids\": [\"29466742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of PC7-positive endosomal compartment at the molecular level undefined\", \"How PC7 and furin are sorted into distinct vesicles unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple studies resolved key non-enzymatic and enzymatic functions: PC7 degrades apoA-V non-enzymatically via an ER–lysosome pathway modulated by Fam20C phosphorylation at Ser505; PC7 sheds CASC4 at KR66 in endosomes/TGN to promote migration; and the EXEXXXL motif in the cytosolic tail—recognized by AP-2—governs endosomal localization and hTfR1 shedding.\",\n      \"evidence\": \"Co-IP, bafilomycin/chloroquine treatment, Pcsk7−/− mice, Fam20C kinase assays (apoA-V); N-glycoproteomics, mutagenesis, migration assays (CASC4); NMR of CT peptides, AP-2 co-IP, alanine scanning (EXEXXXL/AP-2)\",\n      \"pmids\": [\"31945259\", \"32820145\", \"31915245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for AP-2 recognition of the EXEXXXL motif not determined\", \"Whether Fam20C-mediated phosphorylation regulates enzymatic activity on other substrates unknown\", \"In vivo relevance of CASC4 shedding to cancer progression not demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PC7 was shown to bind apoB100 in the ER independently of its catalytic activity and promote VLDL secretion; loss of PC7 diverts apoB100 to proteasomal degradation, triggering UPR, autophagy, and β-oxidation that reduce hepatic lipid accumulation and improve NAFLD outcomes in mice.\",\n      \"evidence\": \"Co-IP in hepatic cells, Pcsk7−/− mouse NAFLD model, GalNAc-ASO hepatocyte knockdown, proteasome inhibition, autophagy assays\",\n      \"pmids\": [\"37967646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of the PC7–apoB100 interaction undefined\", \"Whether the non-enzymatic ER function is conserved for other secretory cargo unknown\", \"Human genetic validation of PCSK7 as a NAFLD modifier lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No full-length structure of PC7 exists, the identity of the unconventional secretory pathway carrier is unknown, and the in vivo hierarchy among enzymatic and non-enzymatic functions in specific tissues remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of PC7\", \"Unconventional secretory route machinery unidentified\", \"Tissue-specific conditional knockouts needed to dissect enzymatic versus non-enzymatic roles\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 8, 9, 10, 15, 16, 17, 21]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11, 18, 21]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [18, 22]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 14, 22]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 20, 24]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [18, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 8, 9, 15, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 13, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 16, 17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [19, 20, 24]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [11, 14, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"BDNF\",\n      \"APOB\",\n      \"APOA5\",\n      \"CASC4\",\n      \"TFRC\",\n      \"AP2A1\",\n      \"FAM20C\",\n      \"VEGFC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}