{"gene":"SEZ6L","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2016,"finding":"SEZ6L is a physiological substrate of BACE1 in neurons. BACE1 cleaves SEZ6L near the membrane, releasing a soluble ectodomain (sSEZ6L). BACE1 inhibition increases neuronal surface levels of SEZ6L (shown by cell surface biotinylation) and reduces sSEZ6L in CSF of BACE1-deficient mice. Mass spectrometry mapped the BACE1 cleavage site in SEZ6L to a position close to the transmembrane domain.","method":"Primary neuron cultures with BACE1 inhibitor treatment, cell surface biotinylation, mass spectrometry cleavage-site mapping, CSF proteomics from BACE1-knockout mice, custom antibody validation","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (in vitro inhibition, in vivo KO, cell surface biotinylation, MS cleavage-site mapping, CSF validation), validated in both cell culture and mouse brain","pmids":["27716410"],"is_preprint":false},{"year":2013,"finding":"SEZ6L is a substrate of BACE1 (and not BACE2) in pancreatic β-cells, with BACE1 mediating ectodomain shedding of SEZ6L; BACE2 has non-redundant roles shedding a distinct substrate set (SEZ6L2, not SEZ6L).","method":"Quantitative proteomics of BACE1/BACE2 loss- and gain-of-function models in β-cells (in vitro and in vivo), systematic sheddome/secretome analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic quantitative proteomics with both loss- and gain-of-function in vitro and in vivo, identifies substrate specificity","pmids":["23430253"],"is_preprint":false},{"year":2018,"finding":"BACE1 controls the surface expression and proteolysis of SEZ6L in neurons; pharmacological BACE1 inhibition increases SEZ6L abundance at the neuronal cell surface (up to 7-fold by SUSPECS click-chemistry glycoprotein labeling), consistent with BACE1-mediated shedding controlling surface levels.","method":"SUSPECS (click chemistry-based surface glycoprotein biotinylation), label-free quantitative mass spectrometry, immunoblot validation in neurons and mouse brain","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — novel orthogonal surface proteomics method combined with MS and immunoblot, replicates and extends substrate finding from prior work","pmids":["29716987"],"is_preprint":false},{"year":2000,"finding":"SEZ6L encodes a 1024 amino acid transmembrane protein with multiple protein-protein interaction and signal transduction domains (determined by full-length cDNA sequencing combined with GENSCAN genomic prediction and RT-PCR). A 428 kb homozygous deletion at 22q12.1 encompassing SEZ6L was identified in a small cell lung cancer cell line, and missense mutations were detected in lung cancer cell lines.","method":"RT-PCR, GENSCAN gene prediction from genomic sequence, deletion breakpoint cloning, mutation screening of cancer cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — full-length cDNA determination with RT-PCR and genomic analysis, domain structure inferred computationally but confirmed by sequence; functional consequence of deletion not directly tested","pmids":["11175339"],"is_preprint":false},{"year":2021,"finding":"Sez6 family members (Sez6, Sez6L, Sez6L2) inhibit complement by two mechanisms: (1) accelerating dissociation of C3 convertases, and (2) acting as cofactors for Factor I to facilitate cleavage of C3b (but not C4b). For the classical pathway, Sez6L is a weak inhibitor compared to Sez6 (strong) and Sez6L2 (moderate). For the alternative pathway, all three family members inhibit at or above the level of the known complement regulator MCP. The CUB and complement control protein (CCP) domains in these proteins provide the structural basis for complement regulatory activity.","method":"In vitro complement inhibition assays (classical and alternative pathway C3b/iC3b opsonization), C3 convertase decay assay, Factor I cofactor assay with C3b and C4b substrates","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro biochemical reconstitution of complement regulatory activity with multiple orthogonal assays (convertase decay, Factor I cofactor activity, opsonization), single lab","pmids":["33936031"],"is_preprint":false},{"year":2021,"finding":"SEZ6L constitutive knockout mice display motor phenotypes in adulthood (altered gait, decreased motor coordination) and increased anxiety-like behaviour, while spatial learning and memory are normal. Gross anatomy and proteome of the adult SEZ6L knockout cerebellum showed no major differences from wild type, suggesting contributions from non-cerebellar regions.","method":"SEZ6L constitutive knockout mouse behavioral testing (gait analysis, rotarod, Morris water maze, anxiety assays), cerebellar proteomics","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean constitutive KO with multiple behavioral readouts and cerebellar proteomics, single lab, no molecular pathway rescue","pmids":["34958451"],"is_preprint":false},{"year":2020,"finding":"Sez6 family triple knockout (lacking Sez6, Sez6L, and Sez6L2) mice show reduced dendritic spine density in the hippocampus and a shift to more immature spine morphologies in somatosensory cortex, along with impaired motor learning, motor coordination decline, impaired working and spatial short-term memory, enhanced stress responsiveness, and reversal learning deficit. This establishes the Sez6 family (including Sez6L) as regulators of dendritic spine structure and cognitive/motor function.","method":"Triple knockout mouse model, dendritic spine morphology analysis, behavioral battery (rotarod, Morris water maze, working memory, anxiety tests)","journal":"Cerebral cortex","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — triple KO with spine morphology and behavioral phenotyping, multiple orthogonal readouts, but attributable to combined loss of all three family members so SEZ6L-specific contribution unclear","pmids":["31711114"],"is_preprint":false},{"year":2018,"finding":"In Niemann-Pick type C (NPC1-null) mouse brains, BACE1-mediated cleavage of Sez6L is enhanced, particularly in cortex, hippocampus, and cerebellum at terminal disease stage. Sez6L and BACE1 co-localize in increased puncta within the endolysosomal pathway in NPC1-null primary neurons, suggesting that a trafficking defect in the endolysosomal pathway drives enhanced BACE1 proteolysis of Sez6L. Sez6L is expressed in Purkinje neurons and its immunostaining is lost upon Purkinje cell neurodegeneration.","method":"Immunoblot quantification of Sez6L and sSez6L in regional brain lysates, immunofluorescence co-localization of Sez6L and BACE1 in primary cortical neurons and brain sections, comparison of NPC1-null vs. wild-type mice at two ages","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic model (NPC1-null vs WT), multiple brain regions, two time points, immunofluorescence and biochemical readouts; mechanism proposed (endolysosomal trafficking) with supportive but not fully reconstituted evidence","pmids":["29979789"],"is_preprint":false},{"year":2022,"finding":"In 5xFAD Alzheimer's disease mouse brains, accumulation of BACE1 in peri-plaque regions and enhanced BACE1 levels do NOT increase proteolysis of Sez6L (or Sez6) compared to WT; instead, Sez6 and Sez6L show altered subcellular distribution in the area of amyloid plaques distinct from APP, BACE1, and LAMP1 localization.","method":"Immunoblot for Sez6L cleavage products in 5xFAD vs. WT mouse brains, immunofluorescence co-localization analysis in brain sections","journal":"Mechanisms of ageing and development","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — negative result for enhanced proteolysis rigorously shown by immunoblot and IF in defined genetic model; single lab, single study","pmids":["35998821"],"is_preprint":false},{"year":2026,"finding":"Sez6l is upregulated in dorsal root ganglion (DRG) in the spared nerve injury (SNI) neuropathic pain model. siRNA-mediated knockdown of Sez6l in SNI mice reduced inflammatory cytokines (IL-6, TNF-α, IL-1β) and alleviated mechanical allodynia and thermal hyperalgesia. ChIP experiments indicated that Foxo1 transcriptionally activates Sez6l. Mechanistically, Sez6l promotes neuropathic pain by activating the Wnt5a/Ca2+ signaling pathway in DRGs.","method":"SNI mouse model, siRNA knockdown, behavioral pain testing (von Frey, thermal hyperalgesia), ELISA for cytokines, ChIP for Foxo1 binding to Sez6l promoter, bioinformatics pathway analysis","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo KO phenotype with behavioral readout, ChIP for upstream regulator, and pathway assignment via Wnt5a/Ca2+; single lab, Wnt5a/Ca2+ pathway link is partly bioinformatic","pmids":["42083568"],"is_preprint":false},{"year":2013,"finding":"RNAi knockdown of SEZ6L in cells affects LDL internalization and/or cellular free cholesterol levels. Overexpression of SEZ6L as a GFP-tagged fusion protein inversely modifies cellular cholesterol levels, and knockdown correlates with altered LDL-receptor levels, indicating SEZ6L has a cholesterol-regulatory function in cells.","method":"RNAi knockdown, LDL internalization assay, free cholesterol measurement, GFP-fusion overexpression, LDL-receptor level measurement","journal":"PLoS genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cell-based RNAi phenotype, single lab, part of a large-scale screen; no direct molecular mechanism for cholesterol regulation established","pmids":["23468663"],"is_preprint":false}],"current_model":"SEZ6L is a single-pass transmembrane neuronal glycoprotein that is a physiological substrate of the protease BACE1, which cleaves it near the membrane to release a soluble ectodomain (sSEZ6L), thereby controlling its cell-surface levels; the intact protein contains CUB and complement control protein (CCP) domains through which it weakly inhibits the complement system by accelerating C3 convertase decay and facilitating Factor I-mediated C3b cleavage; loss of SEZ6L in mice impairs motor coordination and increases anxiety, while combined loss of all Sez6 family members additionally reduces hippocampal dendritic spine density and impairs short-term memory, and in the context of neuropathic pain SEZ6L is transcriptionally induced by Foxo1 and promotes pain signaling through the Wnt5a/Ca2+ pathway in dorsal root ganglia."},"narrative":{"mechanistic_narrative":"SEZ6L is a single-pass transmembrane neuronal glycoprotein whose cell-surface levels are governed by regulated proteolysis: it is a physiological substrate of the protease BACE1 (but not BACE2), which cleaves it near the transmembrane domain to release a soluble ectodomain, such that BACE1 inhibition increases neuronal surface SEZ6L and lowers shed ectodomain in CSF [PMID:27716410, PMID:23430253, PMID:29716987]. Through its CUB and complement control protein (CCP) domains, SEZ6L is a weak regulator of the complement system, accelerating decay of C3 convertases and acting as a cofactor for Factor I-mediated cleavage of C3b [PMID:33936031]. At the organismal level, constitutive loss of SEZ6L impairs motor coordination and increases anxiety while sparing spatial learning, and combined loss of the entire Sez6 family additionally reduces hippocampal dendritic spine density and impairs short-term memory, establishing SEZ6L as a contributor to dendritic spine structure and motor/cognitive behavior [PMID:34958451, PMID:31711114]. SEZ6L proteolysis is altered in neurodegenerative contexts, being enhanced via endolysosomal mistrafficking in Niemann-Pick type C brains [PMID:29979789], and SEZ6L is transcriptionally induced by Foxo1 to promote neuropathic pain through Wnt5a/Ca2+ signaling in dorsal root ganglia [PMID:42083568].","teleology":[{"year":2000,"claim":"Established the basic molecular identity of SEZ6L as a multidomain transmembrane protein and raised the question of a cancer link, framing the protein for later functional study.","evidence":"Full-length cDNA sequencing, GENSCAN prediction, and mutation/deletion screening of lung cancer cell lines","pmids":["11175339"],"confidence":"Medium","gaps":["Functional consequence of the 22q12.1 deletion not directly tested","Domain functions inferred computationally, not biochemically","No tumor-suppressor mechanism demonstrated"]},{"year":2013,"claim":"Resolved which sheddase processes SEZ6L, showing BACE1 (not BACE2) mediates its ectodomain shedding, defining protease specificity.","evidence":"Quantitative proteomics of BACE1/BACE2 loss- and gain-of-function in pancreatic β-cells, in vitro and in vivo","pmids":["23430253"],"confidence":"High","gaps":["Cleavage site not mapped in this study","Functional consequence of shedding not addressed","β-cell context, not neuronal"]},{"year":2013,"claim":"Tested whether SEZ6L has a metabolic role, linking its expression level to LDL internalization and cellular cholesterol.","evidence":"RNAi knockdown and GFP-fusion overexpression with LDL internalization and free cholesterol assays in cells","pmids":["23468663"],"confidence":"Low","gaps":["No direct molecular mechanism for cholesterol regulation established","Part of a large-scale screen, single lab","Not validated in neurons or in vivo"]},{"year":2016,"claim":"Established SEZ6L as a bona fide physiological BACE1 substrate in neurons and mapped the cleavage site, defining how surface levels are controlled.","evidence":"Primary neuron BACE1 inhibition, cell surface biotinylation, MS cleavage-site mapping, CSF proteomics from BACE1-knockout mice","pmids":["27716410"],"confidence":"High","gaps":["Functional consequence of cleavage for SEZ6L activity not shown","No structural detail of the cleaved ectodomain","Signaling downstream of shed ectodomain unknown"]},{"year":2018,"claim":"Quantified the magnitude of BACE1 control over neuronal surface SEZ6L using an orthogonal surface-proteomics method, confirming shedding governs abundance.","evidence":"SUSPECS click-chemistry surface glycoprotein labeling, label-free MS, immunoblot in neurons and mouse brain","pmids":["29716987"],"confidence":"High","gaps":["Does not address physiological role of surface SEZ6L","Mechanism by which shedding alters function not tested"]},{"year":2018,"claim":"Showed SEZ6L proteolysis is disease-context dependent, being enhanced in Niemann-Pick type C brains via endolysosomal co-trafficking with BACE1.","evidence":"Regional immunoblot of Sez6L/sSez6L and IF co-localization of Sez6L and BACE1 in NPC1-null vs WT mouse brains and neurons","pmids":["29979789"],"confidence":"Medium","gaps":["Endolysosomal trafficking mechanism proposed but not fully reconstituted","Causal contribution of enhanced shedding to NPC pathology untested"]},{"year":2020,"claim":"Used family triple-knockout to assign the Sez6 family, including SEZ6L, a role in dendritic spine structure and motor/cognitive function.","evidence":"Sez6/Sez6L/Sez6L2 triple knockout mice with spine morphology analysis and behavioral battery","pmids":["31711114"],"confidence":"Medium","gaps":["SEZ6L-specific contribution confounded by combined family loss","Molecular mechanism linking SEZ6L to spine morphology unknown"]},{"year":2021,"claim":"Defined a molecular activity for SEZ6L as a weak complement regulator acting through convertase decay acceleration and Factor I cofactor activity.","evidence":"In vitro complement inhibition, C3 convertase decay, and Factor I cofactor assays with C3b/C4b substrates","pmids":["33936031"],"confidence":"High","gaps":["Physiological relevance of complement regulation in neurons not shown","Whether shedding modulates complement activity untested","In vitro reconstitution from single lab"]},{"year":2021,"claim":"Isolated SEZ6L-specific in vivo function with a constitutive knockout, revealing motor coordination and anxiety phenotypes independent of cerebellar gross structure.","evidence":"SEZ6L constitutive knockout behavioral testing and cerebellar proteomics","pmids":["34958451"],"confidence":"Medium","gaps":["No molecular pathway rescue","Brain regions driving phenotype not identified","Link to complement or shedding activity not established"]},{"year":2022,"claim":"Showed that elevated BACE1 in an Alzheimer's model does not enhance SEZ6L proteolysis, instead altering its subcellular distribution near plaques, distinguishing AD from NPC contexts.","evidence":"Immunoblot for cleavage products and IF co-localization in 5xFAD vs WT mouse brain","pmids":["35998821"],"confidence":"Medium","gaps":["Mechanism of altered distribution not defined","Negative proteolysis result from single study/lab"]},{"year":2026,"claim":"Connected SEZ6L to neuropathic pain signaling, placing it downstream of Foxo1 transcription and upstream of Wnt5a/Ca2+ activation in dorsal root ganglia.","evidence":"Spared nerve injury model, siRNA knockdown, pain behavioral testing, cytokine ELISA, ChIP for Foxo1, pathway bioinformatics","pmids":["42083568"],"confidence":"Medium","gaps":["Wnt5a/Ca2+ link is partly bioinformatic","Direct mechanism linking SEZ6L protein to Wnt5a signaling not shown","Single lab"]},{"year":null,"claim":"How BACE1-mediated shedding mechanistically links to SEZ6L's complement-regulatory and synaptic functions, and the molecular basis of its cholesterol and pain-signaling roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mechanism connecting ectodomain shedding to downstream SEZ6L function","SEZ6L-specific (vs family) synaptic mechanism undefined","No structural model of SEZ6L domains or its ligands"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":["BACE1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BYH1","full_name":"Seizure 6-like protein","aliases":[],"length_aa":1024,"mass_kda":111.8,"function":"May contribute to specialized endoplasmic reticulum functions in neurons","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9BYH1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEZ6L","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEZ6L","total_profiled":1310},"omim":[{"mim_id":"616667","title":"SEZ6-LIKE PROTEIN 2; SEZ6L2","url":"https://www.omim.org/entry/616667"},{"mim_id":"616666","title":"SEIZURE-RELATED 6, MOUSE, HOMOLOG OF; SEZ6","url":"https://www.omim.org/entry/616666"},{"mim_id":"608397","title":"CUB AND SUSHI MULTIPLE DOMAINS 1; CSMD1","url":"https://www.omim.org/entry/608397"},{"mim_id":"607295","title":"MYOSIN XVIIIB; MYO18B","url":"https://www.omim.org/entry/607295"},{"mim_id":"607021","title":"SEZ6-LIKE PROTEIN; SEZ6L","url":"https://www.omim.org/entry/607021"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":46.3}],"url":"https://www.proteinatlas.org/search/SEZ6L"},"hgnc":{"alias_symbol":["SEZ6L1"],"prev_symbol":[]},"alphafold":{"accession":"Q9BYH1","domains":[{"cath_id":"2.60.120.290","chopping":"280-391","consensus_level":"high","plddt":83.2656,"start":280,"end":391},{"cath_id":"2.60.120.290","chopping":"403-624","consensus_level":"medium","plddt":86.7995,"start":403,"end":624},{"cath_id":"2.60.120.290","chopping":"627-741","consensus_level":"medium","plddt":85.2282,"start":627,"end":741},{"cath_id":"2.10.70.10","chopping":"755-803","consensus_level":"medium","plddt":84.9378,"start":755,"end":803},{"cath_id":"2.10.70.10","chopping":"816-868","consensus_level":"high","plddt":84.9268,"start":816,"end":868},{"cath_id":"2.10.70.10","chopping":"874-933","consensus_level":"high","plddt":84.716,"start":874,"end":933}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYH1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYH1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYH1-F1-predicted_aligned_error_v6.png","plddt_mean":68.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEZ6L","jax_strain_url":"https://www.jax.org/strain/search?query=SEZ6L"},"sequence":{"accession":"Q9BYH1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BYH1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BYH1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYH1"}},"corpus_meta":[{"pmid":"18158559","id":"PMC_18158559","title":"DNA 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is a physiological substrate of BACE1 in neurons. BACE1 cleaves SEZ6L near the membrane, releasing a soluble ectodomain (sSEZ6L). BACE1 inhibition increases neuronal surface levels of SEZ6L (shown by cell surface biotinylation) and reduces sSEZ6L in CSF of BACE1-deficient mice. Mass spectrometry mapped the BACE1 cleavage site in SEZ6L to a position close to the transmembrane domain.\",\n      \"method\": \"Primary neuron cultures with BACE1 inhibitor treatment, cell surface biotinylation, mass spectrometry cleavage-site mapping, CSF proteomics from BACE1-knockout mice, custom antibody validation\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (in vitro inhibition, in vivo KO, cell surface biotinylation, MS cleavage-site mapping, CSF validation), validated in both cell culture and mouse brain\",\n      \"pmids\": [\"27716410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SEZ6L is a substrate of BACE1 (and not BACE2) in pancreatic β-cells, with BACE1 mediating ectodomain shedding of SEZ6L; BACE2 has non-redundant roles shedding a distinct substrate set (SEZ6L2, not SEZ6L).\",\n      \"method\": \"Quantitative proteomics of BACE1/BACE2 loss- and gain-of-function models in β-cells (in vitro and in vivo), systematic sheddome/secretome analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic quantitative proteomics with both loss- and gain-of-function in vitro and in vivo, identifies substrate specificity\",\n      \"pmids\": [\"23430253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BACE1 controls the surface expression and proteolysis of SEZ6L in neurons; pharmacological BACE1 inhibition increases SEZ6L abundance at the neuronal cell surface (up to 7-fold by SUSPECS click-chemistry glycoprotein labeling), consistent with BACE1-mediated shedding controlling surface levels.\",\n      \"method\": \"SUSPECS (click chemistry-based surface glycoprotein biotinylation), label-free quantitative mass spectrometry, immunoblot validation in neurons and mouse brain\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — novel orthogonal surface proteomics method combined with MS and immunoblot, replicates and extends substrate finding from prior work\",\n      \"pmids\": [\"29716987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SEZ6L encodes a 1024 amino acid transmembrane protein with multiple protein-protein interaction and signal transduction domains (determined by full-length cDNA sequencing combined with GENSCAN genomic prediction and RT-PCR). A 428 kb homozygous deletion at 22q12.1 encompassing SEZ6L was identified in a small cell lung cancer cell line, and missense mutations were detected in lung cancer cell lines.\",\n      \"method\": \"RT-PCR, GENSCAN gene prediction from genomic sequence, deletion breakpoint cloning, mutation screening of cancer cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — full-length cDNA determination with RT-PCR and genomic analysis, domain structure inferred computationally but confirmed by sequence; functional consequence of deletion not directly tested\",\n      \"pmids\": [\"11175339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sez6 family members (Sez6, Sez6L, Sez6L2) inhibit complement by two mechanisms: (1) accelerating dissociation of C3 convertases, and (2) acting as cofactors for Factor I to facilitate cleavage of C3b (but not C4b). For the classical pathway, Sez6L is a weak inhibitor compared to Sez6 (strong) and Sez6L2 (moderate). For the alternative pathway, all three family members inhibit at or above the level of the known complement regulator MCP. The CUB and complement control protein (CCP) domains in these proteins provide the structural basis for complement regulatory activity.\",\n      \"method\": \"In vitro complement inhibition assays (classical and alternative pathway C3b/iC3b opsonization), C3 convertase decay assay, Factor I cofactor assay with C3b and C4b substrates\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro biochemical reconstitution of complement regulatory activity with multiple orthogonal assays (convertase decay, Factor I cofactor activity, opsonization), single lab\",\n      \"pmids\": [\"33936031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEZ6L constitutive knockout mice display motor phenotypes in adulthood (altered gait, decreased motor coordination) and increased anxiety-like behaviour, while spatial learning and memory are normal. Gross anatomy and proteome of the adult SEZ6L knockout cerebellum showed no major differences from wild type, suggesting contributions from non-cerebellar regions.\",\n      \"method\": \"SEZ6L constitutive knockout mouse behavioral testing (gait analysis, rotarod, Morris water maze, anxiety assays), cerebellar proteomics\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean constitutive KO with multiple behavioral readouts and cerebellar proteomics, single lab, no molecular pathway rescue\",\n      \"pmids\": [\"34958451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sez6 family triple knockout (lacking Sez6, Sez6L, and Sez6L2) mice show reduced dendritic spine density in the hippocampus and a shift to more immature spine morphologies in somatosensory cortex, along with impaired motor learning, motor coordination decline, impaired working and spatial short-term memory, enhanced stress responsiveness, and reversal learning deficit. This establishes the Sez6 family (including Sez6L) as regulators of dendritic spine structure and cognitive/motor function.\",\n      \"method\": \"Triple knockout mouse model, dendritic spine morphology analysis, behavioral battery (rotarod, Morris water maze, working memory, anxiety tests)\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — triple KO with spine morphology and behavioral phenotyping, multiple orthogonal readouts, but attributable to combined loss of all three family members so SEZ6L-specific contribution unclear\",\n      \"pmids\": [\"31711114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Niemann-Pick type C (NPC1-null) mouse brains, BACE1-mediated cleavage of Sez6L is enhanced, particularly in cortex, hippocampus, and cerebellum at terminal disease stage. Sez6L and BACE1 co-localize in increased puncta within the endolysosomal pathway in NPC1-null primary neurons, suggesting that a trafficking defect in the endolysosomal pathway drives enhanced BACE1 proteolysis of Sez6L. Sez6L is expressed in Purkinje neurons and its immunostaining is lost upon Purkinje cell neurodegeneration.\",\n      \"method\": \"Immunoblot quantification of Sez6L and sSez6L in regional brain lysates, immunofluorescence co-localization of Sez6L and BACE1 in primary cortical neurons and brain sections, comparison of NPC1-null vs. wild-type mice at two ages\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic model (NPC1-null vs WT), multiple brain regions, two time points, immunofluorescence and biochemical readouts; mechanism proposed (endolysosomal trafficking) with supportive but not fully reconstituted evidence\",\n      \"pmids\": [\"29979789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In 5xFAD Alzheimer's disease mouse brains, accumulation of BACE1 in peri-plaque regions and enhanced BACE1 levels do NOT increase proteolysis of Sez6L (or Sez6) compared to WT; instead, Sez6 and Sez6L show altered subcellular distribution in the area of amyloid plaques distinct from APP, BACE1, and LAMP1 localization.\",\n      \"method\": \"Immunoblot for Sez6L cleavage products in 5xFAD vs. WT mouse brains, immunofluorescence co-localization analysis in brain sections\",\n      \"journal\": \"Mechanisms of ageing and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — negative result for enhanced proteolysis rigorously shown by immunoblot and IF in defined genetic model; single lab, single study\",\n      \"pmids\": [\"35998821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Sez6l is upregulated in dorsal root ganglion (DRG) in the spared nerve injury (SNI) neuropathic pain model. siRNA-mediated knockdown of Sez6l in SNI mice reduced inflammatory cytokines (IL-6, TNF-α, IL-1β) and alleviated mechanical allodynia and thermal hyperalgesia. ChIP experiments indicated that Foxo1 transcriptionally activates Sez6l. Mechanistically, Sez6l promotes neuropathic pain by activating the Wnt5a/Ca2+ signaling pathway in DRGs.\",\n      \"method\": \"SNI mouse model, siRNA knockdown, behavioral pain testing (von Frey, thermal hyperalgesia), ELISA for cytokines, ChIP for Foxo1 binding to Sez6l promoter, bioinformatics pathway analysis\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo KO phenotype with behavioral readout, ChIP for upstream regulator, and pathway assignment via Wnt5a/Ca2+; single lab, Wnt5a/Ca2+ pathway link is partly bioinformatic\",\n      \"pmids\": [\"42083568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RNAi knockdown of SEZ6L in cells affects LDL internalization and/or cellular free cholesterol levels. Overexpression of SEZ6L as a GFP-tagged fusion protein inversely modifies cellular cholesterol levels, and knockdown correlates with altered LDL-receptor levels, indicating SEZ6L has a cholesterol-regulatory function in cells.\",\n      \"method\": \"RNAi knockdown, LDL internalization assay, free cholesterol measurement, GFP-fusion overexpression, LDL-receptor level measurement\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cell-based RNAi phenotype, single lab, part of a large-scale screen; no direct molecular mechanism for cholesterol regulation established\",\n      \"pmids\": [\"23468663\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEZ6L is a single-pass transmembrane neuronal glycoprotein that is a physiological substrate of the protease BACE1, which cleaves it near the membrane to release a soluble ectodomain (sSEZ6L), thereby controlling its cell-surface levels; the intact protein contains CUB and complement control protein (CCP) domains through which it weakly inhibits the complement system by accelerating C3 convertase decay and facilitating Factor I-mediated C3b cleavage; loss of SEZ6L in mice impairs motor coordination and increases anxiety, while combined loss of all Sez6 family members additionally reduces hippocampal dendritic spine density and impairs short-term memory, and in the context of neuropathic pain SEZ6L is transcriptionally induced by Foxo1 and promotes pain signaling through the Wnt5a/Ca2+ pathway in dorsal root ganglia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEZ6L is a single-pass transmembrane neuronal glycoprotein whose cell-surface levels are governed by regulated proteolysis: it is a physiological substrate of the protease BACE1 (but not BACE2), which cleaves it near the transmembrane domain to release a soluble ectodomain, such that BACE1 inhibition increases neuronal surface SEZ6L and lowers shed ectodomain in CSF [#0, #1, #2]. Through its CUB and complement control protein (CCP) domains, SEZ6L is a weak regulator of the complement system, accelerating decay of C3 convertases and acting as a cofactor for Factor I-mediated cleavage of C3b [#4]. At the organismal level, constitutive loss of SEZ6L impairs motor coordination and increases anxiety while sparing spatial learning, and combined loss of the entire Sez6 family additionally reduces hippocampal dendritic spine density and impairs short-term memory, establishing SEZ6L as a contributor to dendritic spine structure and motor/cognitive behavior [#5, #6]. SEZ6L proteolysis is altered in neurodegenerative contexts, being enhanced via endolysosomal mistrafficking in Niemann-Pick type C brains [#7], and SEZ6L is transcriptionally induced by Foxo1 to promote neuropathic pain through Wnt5a/Ca2+ signaling in dorsal root ganglia [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the basic molecular identity of SEZ6L as a multidomain transmembrane protein and raised the question of a cancer link, framing the protein for later functional study.\",\n      \"evidence\": \"Full-length cDNA sequencing, GENSCAN prediction, and mutation/deletion screening of lung cancer cell lines\",\n      \"pmids\": [\"11175339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the 22q12.1 deletion not directly tested\", \"Domain functions inferred computationally, not biochemically\", \"No tumor-suppressor mechanism demonstrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved which sheddase processes SEZ6L, showing BACE1 (not BACE2) mediates its ectodomain shedding, defining protease specificity.\",\n      \"evidence\": \"Quantitative proteomics of BACE1/BACE2 loss- and gain-of-function in pancreatic β-cells, in vitro and in vivo\",\n      \"pmids\": [\"23430253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site not mapped in this study\", \"Functional consequence of shedding not addressed\", \"β-cell context, not neuronal\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Tested whether SEZ6L has a metabolic role, linking its expression level to LDL internalization and cellular cholesterol.\",\n      \"evidence\": \"RNAi knockdown and GFP-fusion overexpression with LDL internalization and free cholesterol assays in cells\",\n      \"pmids\": [\"23468663\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct molecular mechanism for cholesterol regulation established\", \"Part of a large-scale screen, single lab\", \"Not validated in neurons or in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established SEZ6L as a bona fide physiological BACE1 substrate in neurons and mapped the cleavage site, defining how surface levels are controlled.\",\n      \"evidence\": \"Primary neuron BACE1 inhibition, cell surface biotinylation, MS cleavage-site mapping, CSF proteomics from BACE1-knockout mice\",\n      \"pmids\": [\"27716410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of cleavage for SEZ6L activity not shown\", \"No structural detail of the cleaved ectodomain\", \"Signaling downstream of shed ectodomain unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Quantified the magnitude of BACE1 control over neuronal surface SEZ6L using an orthogonal surface-proteomics method, confirming shedding governs abundance.\",\n      \"evidence\": \"SUSPECS click-chemistry surface glycoprotein labeling, label-free MS, immunoblot in neurons and mouse brain\",\n      \"pmids\": [\"29716987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address physiological role of surface SEZ6L\", \"Mechanism by which shedding alters function not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed SEZ6L proteolysis is disease-context dependent, being enhanced in Niemann-Pick type C brains via endolysosomal co-trafficking with BACE1.\",\n      \"evidence\": \"Regional immunoblot of Sez6L/sSez6L and IF co-localization of Sez6L and BACE1 in NPC1-null vs WT mouse brains and neurons\",\n      \"pmids\": [\"29979789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endolysosomal trafficking mechanism proposed but not fully reconstituted\", \"Causal contribution of enhanced shedding to NPC pathology untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Used family triple-knockout to assign the Sez6 family, including SEZ6L, a role in dendritic spine structure and motor/cognitive function.\",\n      \"evidence\": \"Sez6/Sez6L/Sez6L2 triple knockout mice with spine morphology analysis and behavioral battery\",\n      \"pmids\": [\"31711114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SEZ6L-specific contribution confounded by combined family loss\", \"Molecular mechanism linking SEZ6L to spine morphology unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a molecular activity for SEZ6L as a weak complement regulator acting through convertase decay acceleration and Factor I cofactor activity.\",\n      \"evidence\": \"In vitro complement inhibition, C3 convertase decay, and Factor I cofactor assays with C3b/C4b substrates\",\n      \"pmids\": [\"33936031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of complement regulation in neurons not shown\", \"Whether shedding modulates complement activity untested\", \"In vitro reconstitution from single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Isolated SEZ6L-specific in vivo function with a constitutive knockout, revealing motor coordination and anxiety phenotypes independent of cerebellar gross structure.\",\n      \"evidence\": \"SEZ6L constitutive knockout behavioral testing and cerebellar proteomics\",\n      \"pmids\": [\"34958451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular pathway rescue\", \"Brain regions driving phenotype not identified\", \"Link to complement or shedding activity not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that elevated BACE1 in an Alzheimer's model does not enhance SEZ6L proteolysis, instead altering its subcellular distribution near plaques, distinguishing AD from NPC contexts.\",\n      \"evidence\": \"Immunoblot for cleavage products and IF co-localization in 5xFAD vs WT mouse brain\",\n      \"pmids\": [\"35998821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of altered distribution not defined\", \"Negative proteolysis result from single study/lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected SEZ6L to neuropathic pain signaling, placing it downstream of Foxo1 transcription and upstream of Wnt5a/Ca2+ activation in dorsal root ganglia.\",\n      \"evidence\": \"Spared nerve injury model, siRNA knockdown, pain behavioral testing, cytokine ELISA, ChIP for Foxo1, pathway bioinformatics\",\n      \"pmids\": [\"42083568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Wnt5a/Ca2+ link is partly bioinformatic\", \"Direct mechanism linking SEZ6L protein to Wnt5a signaling not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BACE1-mediated shedding mechanistically links to SEZ6L's complement-regulatory and synaptic functions, and the molecular basis of its cholesterol and pain-signaling roles, remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanism connecting ectodomain shedding to downstream SEZ6L function\", \"SEZ6L-specific (vs family) synaptic mechanism undefined\", \"No structural model of SEZ6L domains or its ligands\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BACE1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}