{"gene":"SURF4","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1995,"finding":"SURF4 (Surf-4) is a ~30 kDa integral membrane protein with at least two (predicted seven) transmembrane domains, a C-terminal double-lysine ER retrieval motif, and localizes to the ER (not plasma membrane), as shown by salt/detergent microsomal fractionation and immunofluorescence of myc-tagged chimeras.","method":"In vitro translation, salt/detergent extraction, proteolysis protection assay, immunofluorescence of myc-tagged Surf4 transfectants","journal":"Molecular membrane biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical fractionation and proteolysis protection with immunofluorescence confirmation in one study, single lab","pmids":["7540914"],"is_preprint":false},{"year":2008,"finding":"SURF4 physically interacts with ERGIC-53 and p24 proteins in the early secretory pathway. Co-silencing SURF4 with ERGIC-53, or silencing the p24 family member p25, causes reduced ERGIC cluster number and Golgi fragmentation, partial redistribution of COPI (but not Golgi matrix proteins) to the cytosol, and partial brefeldin-A resistance of the cis-Golgi—without blocking anterograde transport. Live imaging showed decreased ERGIC cluster stability after p25 knockdown.","method":"Co-immunoprecipitation, siRNA knockdown, live-cell imaging, immunofluorescence, brefeldin A treatment","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction plus functional epistasis with multiple knockdown conditions and live imaging, replicated across multiple perturbations in one rigorous study","pmids":["18287528"],"is_preprint":false},{"year":2018,"finding":"SURF4 is the primary ER cargo receptor mediating efficient secretion of PCSK9 in HEK293T cells. SURF4 localizes to the early secretory pathway, physically interacts with PCSK9, and its deletion causes ER accumulation and reduced extracellular secretion of PCSK9, rescued by SURF4 cDNA re-expression.","method":"Proximity-dependent biotinylation (BioID) proteomics, genome-scale CRISPR screen, multiple independent sgRNAs, clonal SURF4-deficient cell lines, functional rescue with SURF4 cDNA, co-immunoprecipitation, subcellular fractionation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (BioID, CRISPR screen, co-IP, rescue) in a single rigorous study","pmids":["30251625"],"is_preprint":false},{"year":2018,"finding":"SURF4 functions as a cargo receptor that binds amino-terminal tripeptide motifs (ER-ESCAPE motifs) exposed after signal sequence cleavage on soluble cargo proteins, enabling their preferential ER export. Binding affinity scales with aggregation propensity of the cargo; single amino acid changes in the tripeptide alter ER retention. Human cells lacking SURF4 lose preferential trafficking of strong ER-ESCAPE motif cargoes; re-expression of SURF4 or yeast Erv29p rescues this.","method":"Mutagenesis of N-terminal tripeptide motifs, SURF4 knockout human cells, functional rescue with SURF4 or Erv29p, systematic survey of 8,000 tripeptide variants, secretion assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis across thousands of motif variants combined with KO rescue, multiple orthogonal methods in one study","pmids":["30086131"],"is_preprint":false},{"year":2018,"finding":"SFT-4 (C. elegans SURF4 homolog) localizes predominantly to ER exit sites (ERES) and physically interacts with the yolk lipoprotein VIT-2, promoting its ER export. Mammalian SURF4 physically interacts with apolipoprotein B and its loss causes ER accumulation of apoB in human hepatic HepG2 cells. Loss of SFT-4/SURF4 also reduces the number of COPII-positive ERES.","method":"Co-immunoprecipitation, immunofluorescence colocalization, in vivo interaction assay in C. elegans, siRNA knockdown in HepG2 cells, ERES quantification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal evidence from two organisms, co-IP and localization, functional ERES phenotype confirmed","pmids":["29643117"],"is_preprint":false},{"year":2012,"finding":"SURF4 associates with STIM1 in the ER. Deletion of Surf4 in DT40 B cells results in markedly increased store-operated Ca²⁺ entry (SOCE) and facilitated STIM1 clustering upon store depletion, indicating SURF4 negatively modulates STIM1-mediated SOCE.","method":"Affinity purification for STIM1-binding proteins, co-immunoprecipitation, Surf4 knockout DT40 B cells, Ca²⁺ entry measurements","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification plus KO functional phenotype in single lab study","pmids":["22609200"],"is_preprint":false},{"year":2020,"finding":"SURF4 functions as an ER cargo receptor mediating efficient secretion of erythropoietin (EPO). SURF4 disruption causes intracellular EPO accumulation in the ER and reduced extracellular EPO; SURF4 and EPO physically interact. SURF4 overexpression increases EPO secretion. These findings were confirmed in multiple cell lines including endogenous EPO-secreting Hep3B cells under hypoxia.","method":"Genome-scale CRISPR screen, multiple independent sgRNAs, SURF4 cDNA rescue, co-immunoprecipitation, subcellular fractionation/immunofluorescence, endogenous EPO secretion assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus multiple sgRNAs, rescue, co-IP, subcellular fractionation, confirmed in endogenous system","pmids":["32989016"],"is_preprint":false},{"year":2020,"finding":"Homozygous Surf4 knockout mice are embryonic lethal (between E3.5 and E9.5), demonstrating SURF4 is essential for early embryonic development in vivo, and implying additional essential cargoes or functions beyond known ones.","method":"CRISPR/Cas9 germline knockout mice, embryonic staging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined embryonic lethal phenotype, single lab","pmids":["31978056"],"is_preprint":false},{"year":2021,"finding":"Progranulin interacts with prosaposin in the ER lumen; prosaposin physically interacts with SURF4, and SURF4 is critical for efficient ER exit of both progranulin and prosaposin. Thus SURF4 mediates lysosomal delivery of progranulin via a prosaposin relay.","method":"Co-immunoprecipitation, SURF4 knockdown/knockout, subcellular fractionation, secretion assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus KD/KO phenotype in single lab study","pmids":["34919127"],"is_preprint":false},{"year":2021,"finding":"Hepatic liver-specific Surf4 knockout mice show no effect on PCSK9 secretion (negative finding for this model), but a significant reduction in plasma cholesterol, triglycerides, and apoB due to impaired VLDL secretion. Surf4 co-immunoprecipitates and colocalizes with apolipoprotein B100 in human hepatocytes. Knockdown of hepatic Surf4 in Ldlr-/- mice reduces atherosclerosis without causing liver lipid accumulation.","method":"Liver-specific Surf4 knockout mice, co-immunoprecipitation, immunofluorescence colocalization, siRNA knockdown, lipid measurements, atherosclerosis quantification","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO confirmed by co-IP and colocalization plus atherosclerosis readout; consistent with parallel studies","pmids":["34118252"],"is_preprint":false},{"year":2022,"finding":"SURF4 induces a distinct tubular ERGIC (t-ERGIC) that is ERGIC-53-negative but Rab1A/B-positive, with high surface-to-volume ratio and fast ER-to-Golgi travel speed. SURF4 recognizes N-terminal signals of soluble cargoes, co-clusters with them to expand the ER exit site, and t-ERGIC biogenesis and cargo selectivity both depend on SURF4. The fast SURF4-dependent transport is antagonized by KDEL-mediated ER retrieval.","method":"Live-cell superresolution imaging, SURF4 KO/knockdown, SURF4 rescue, N-terminal signal mutagenesis, trafficking kinetics assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging with superresolution plus KO/rescue and mutagenesis, multiple orthogonal methods in one study","pmids":["35051356"],"is_preprint":false},{"year":2022,"finding":"SURF4 facilitates ER export of Sonic Hedgehog (Shh) via an ER export signal, and proteoglycans promote dissociation of SURF4 from Shh at the Golgi, constituting a SURF4-to-proteoglycan relay mechanism for Shh secretion.","method":"Co-immunoprecipitation, ER export signal mutagenesis, proteoglycan competition assays, subcellular fractionation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus mutagenesis and Golgi dissociation assay, single lab study","pmids":["35271396"],"is_preprint":false},{"year":2022,"finding":"Surf4 promotes ER export of proinsulin in pancreatic β-cells by recruiting proinsulin to ERES. Surf4 expression is upregulated under high-glucose conditions. Surf4 forms oligomers and physically interacts with both proinsulin and Sec12 (essential for COPII vesicle formation), suggesting it delivers proinsulin into COPII vesicles cooperatively with Sec12. Surf4 knockdown causes proinsulin ER retention and decreased mature insulin and insulin secretion.","method":"Surf4 knockdown, co-immunoprecipitation with proinsulin and Sec12, immunofluorescence colocalization at ERES, insulin secretion assays, oligomerization assays","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP with two binding partners plus KD phenotype and ERES localization, multiple orthogonal methods","pmids":["35562580"],"is_preprint":false},{"year":2022,"finding":"Hepatic Surf4-conditional knockout mice show ~60% reduction in plasma PCSK9, ~50% increase in hepatic LDLR, and a severe defect in hepatic lipoprotein secretion (APOB-containing lipoproteins), causing marked reduction in plasma cholesterol and triglycerides. Acute depletion by liver-targeted CRISPR/Cas9 or siRNA confirms these findings in vivo.","method":"Conditional KO mice (Surf4 Alb-Cre), acute CRISPR/Cas9 and siRNA depletion in adult mice, plasma PCSK9/LDLR/lipid measurements, lipoprotein metabolism characterization","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO confirmed by two orthogonal acute depletion methods, replicated across models","pmids":["36193893"],"is_preprint":false},{"year":2023,"finding":"SURF4 traffics a broad range of secretory cargoes in HuH7 hepatocytes, as identified by mass spectrometry of conditioned media and cell lysates from SURF4 CRISPR knockout cells. Cargo recognition is governed by complex mechanisms rather than a universal binding motif.","method":"CRISPR gene inactivation, mass spectrometry of conditioned media and cell lysates","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic proteomics of KO cells, single lab study","pmids":["37844105"],"is_preprint":false},{"year":2023,"finding":"Intestinal Surf4 is essential for apolipoprotein (ApoA1, ApoB48, PRAP1) transport and chylomicron/HDL secretion. Intestine-specific Surf4 KO mice display ectopic lipid deposition in the small intestine and hypolipidemia. Surf4 co-localizes with apoB and co-immunoprecipitates with apoB48 in differentiated Caco-2 cells.","method":"Intestine-specific KO mice, co-immunoprecipitation, immunofluorescence colocalization, proteomics, lipid measurements","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo intestinal KO with co-IP and colocalization in cell model, multiple orthogonal methods","pmids":["38042368"],"is_preprint":false},{"year":2023,"finding":"Surf4 collaborates with derlin-2 and derlin-1 in ERAD: Surf4 acts downstream of derlin-2 and derlin-1 to mediate COX-2 translocation from the ER lumen to the cytosol. Surf4 knockdown impedes COX-2 ubiquitylation and its interaction with caveolin-1 and p97 in the cytosol. Surf4 and p97 preferentially interact with non-glycosylated COX-2.","method":"CRISPR library screen, siRNA knockdown, co-immunoprecipitation, ubiquitylation assays, N-glycosylation mutant analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus co-IP and knockdown epistasis, single lab study","pmids":["37676109"],"is_preprint":false},{"year":2024,"finding":"SURF4 recruits different SEC24 paralogs of the COPII coat for export of different cargoes: PCSK9 requires both SURF4 and co-receptor TMED10 for export via SEC24A, whereas Cab45 and NUCB1 require SEC24C/D. ER export signals of Cab45 and NUCB1 bind co-translationally to a lumenal pocket of SURF4, contrasting models requiring cargo folding before receptor engagement.","method":"Epistasis using SEC24 paralog-specific mutants, co-immunoprecipitation with TMED10, mutagenesis of lumenal SURF4 pocket, co-translational binding assays, secretion assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of receptor pocket, functional dissection of SEC24 paralog usage, co-translational binding assay, multiple cargoes tested","pmids":["39531033"],"is_preprint":false},{"year":2024,"finding":"Hepatic SURF4 facilitates SAA1 (serum amyloid A1) secretion. SURF4 co-immunoprecipitates and colocalizes with SAA1. Surf4 liver-specific KO reduces SAA1 secretion from hepatocytes, decreasing hepatic stellate cell (HSC) activation (via SAA1-TLR2 signaling) and attenuating liver fibrosis.","method":"Conditional Surf4 KO mice, co-immunoprecipitation, colocalization, conditioned medium assays, SAA1 knockdown epistasis, TLR2 knockdown in LX-2 cells, CCl4-fibrosis model","journal":"Research (Washington, D.C.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with co-IP plus epistasis knockdown experiments confirming SAA1-TLR2 pathway, multiple orthogonal methods","pmids":["39105051"],"is_preprint":false},{"year":2021,"finding":"Surf4 facilitates somatic cell reprogramming to iPSCs by activating the ER stress response (UPR) at an early stage of reprogramming. Surf4 co-expressed with OSKM activates Hspa5 and spliced Xbp1; blocking UPR compromises Surf4's reprogramming effect.","method":"Secondary reprogramming system, RNA-seq, qPCR, Western blot, alkaline phosphatase staining, UPR inhibition experiments","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KO/OE with transcriptomic validation and UPR inhibition rescue, but indirect pathway placement, single lab","pmids":["34585448"],"is_preprint":false},{"year":2025,"finding":"YIPF5 directly interacts with SURF4 and negatively regulates SURF4-mediated ER export. YIPF5 depletion alters SURF4 localization, causing elongated ERGIC53- and Rab1-positive tubules from COPII-labeled ER exit sites, and kinetic analysis shows enhanced SURF4-mediated ER export in YIPF5 KO cells.","method":"Co-immunoprecipitation (direct interaction), YIPF5 KO cells, live-cell imaging of ERGIC tubules, kinetic secretion assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus KO imaging and kinetic assays, preprint, single lab","pmids":["bio_10.1101_2025.06.11.659036"],"is_preprint":true}],"current_model":"SURF4 is a polytopic ER-resident transmembrane cargo receptor that selectively captures soluble secretory proteins bearing N-terminal tripeptide ER-ESCAPE motifs via a lumenal binding pocket (engaging cargoes co-translationally), recruits them into COPII-coated vesicles by engaging specific SEC24 paralogs (SEC24A for PCSK9/TMED10 co-receptor pathway; SEC24C/D for Cab45/NUCB1), drives formation of a tubular ERGIC that accelerates ER-to-Golgi transport, physically interacts with ERGIC-53 and p24 proteins to maintain ERGIC/Golgi architecture via COPI recruitment, mediates secretion of a broad cargo repertoire including PCSK9, apolipoprotein B, EPO, proinsulin, progranulin/prosaposin, SAA1, and Shh, and also participates in ERAD by cooperating with derlin-2/derlin-1 to retrotranslocate COX-2 to the cytosol; additionally, SURF4 negatively modulates STIM1-dependent store-operated Ca²⁺ entry and is negatively regulated by YIPF5."},"narrative":{"mechanistic_narrative":"SURF4 is an ER-resident polytopic transmembrane cargo receptor that selectively captures soluble secretory proteins and delivers them into the COPII-dependent ER-to-Golgi pathway [PMID:7540914, PMID:30251625, PMID:30086131]. It recognizes cargo through N-terminal tripeptide ER-ESCAPE motifs exposed after signal-sequence cleavage, with binding affinity scaling to cargo aggregation propensity and single residue changes altering ER retention [PMID:30086131]; ER export signals can engage a lumenal SURF4 pocket co-translationally rather than requiring prior cargo folding [PMID:39531033]. SURF4 co-clusters with bound cargo to expand ER exit sites and nucleates a distinct tubular ERGIC (ERGIC-53-negative, Rab1A/B-positive) that accelerates ER-to-Golgi transport, a process antagonized by KDEL-mediated retrieval [PMID:35051356]. Cargo is loaded into COPII vesicles via paralog-selective SEC24 engagement and accessory factors, including a TMED10 co-receptor route for PCSK9 [PMID:39531033, PMID:35562580]. Through this machinery SURF4 mediates secretion of a broad cargo repertoire — PCSK9, apolipoprotein B and VLDL/chylomicron lipoproteins, erythropoietin, proinsulin, the progranulin/prosaposin pair, Sonic Hedgehog, and SAA1 — with cargo recognition governed by complex determinants beyond a single universal motif [PMID:30251625, PMID:29643117, PMID:32989016, PMID:34919127, PMID:34118252, PMID:35271396, PMID:35562580, PMID:37844105, PMID:38042368, PMID:39105051]. SURF4 also functions in the ERGIC/Golgi architecture maintenance via interactions with ERGIC-53 and p24 proteins and COPI recruitment [PMID:18287528], cooperates with derlin-2/derlin-1 to retrotranslocate COX-2 during ERAD [PMID:37676109], and negatively modulates STIM1-dependent store-operated Ca²⁺ entry [PMID:22609200]. SURF4-mediated export is negatively regulated by direct binding of YIPF5 [PMID:bio_10.1101_2025.06.11.659036]. Loss of Surf4 is embryonic lethal in mice, and tissue-specific deletion lowers plasma cholesterol, triglycerides and PCSK9 and attenuates atherosclerosis and liver fibrosis [PMID:31978056, PMID:34118252, PMID:36193893, PMID:39105051].","teleology":[{"year":1995,"claim":"Established the basic identity of SURF4 as an ER membrane protein, defining where in the cell it could act before any function was known.","evidence":"In vitro translation, microsomal fractionation, proteolysis protection, and immunofluorescence of myc-tagged chimeras","pmids":["7540914"],"confidence":"Medium","gaps":["No cargo or pathway function assigned","Transmembrane topology only predicted, not resolved"]},{"year":2008,"claim":"Showed SURF4 is not merely ER-resident but a structural participant in early secretory architecture, physically engaging ERGIC-53 and p24 proteins to maintain ERGIC clusters and Golgi integrity.","evidence":"Co-IP, siRNA co-silencing, live imaging, and brefeldin A assays in cultured cells","pmids":["18287528"],"confidence":"High","gaps":["Did not identify soluble cargoes","Mechanism of COPI recruitment not defined"]},{"year":2012,"claim":"Revealed a non-trafficking role by linking SURF4 to ER calcium signaling, showing it restrains STIM1-mediated store-operated Ca²⁺ entry.","evidence":"Affinity purification, co-IP, and Ca²⁺ entry measurements in Surf4-knockout DT40 B cells","pmids":["22609200"],"confidence":"Medium","gaps":["Molecular basis of STIM1 modulation unresolved","Single cell-type system"]},{"year":2018,"claim":"Defined SURF4 as a selective cargo receptor and decoded its recognition logic — N-terminal ER-ESCAPE tripeptide motifs exposed after signal cleavage — establishing how it discriminates soluble export clients.","evidence":"Systematic mutagenesis of ~8,000 tripeptide variants, KO human cells, and rescue with SURF4 or yeast Erv29p; parallel BioID/CRISPR/co-IP studies identifying PCSK9 and apoB/VIT-2 as cargoes","pmids":["30086131","30251625","29643117"],"confidence":"High","gaps":["Structural basis of motif binding pocket not resolved","Did not explain cargoes lacking strong motifs"]},{"year":2020,"claim":"Extended the cargo repertoire to erythropoietin and demonstrated organismal essentiality, showing SURF4 function is required for early embryonic development.","evidence":"Genome-scale CRISPR screen, multiple sgRNAs, rescue, co-IP for EPO; CRISPR/Cas9 germline knockout mice","pmids":["32989016","31978056"],"confidence":"High","gaps":["Essential embryonic cargo not identified","EPO recognition determinants undefined"]},{"year":2021,"claim":"Broadened cargo classes (progranulin via a prosaposin relay) and connected SURF4 to ER stress signaling during cell reprogramming, indicating roles beyond constitutive secretion.","evidence":"Co-IP, KD/KO secretion assays for progranulin/prosaposin; reprogramming system with RNA-seq and UPR inhibition","pmids":["34919127","34585448"],"confidence":"Medium","gaps":["Reprogramming role is indirect pathway placement","How SURF4 activates UPR unclear"]},{"year":2022,"claim":"Resolved the trafficking machinery in mechanistic and physiological depth — SURF4 nucleates a fast tubular ERGIC, cooperates with Sec12 for proinsulin export, relays Shh to proteoglycans, and drives hepatic lipoprotein secretion in vivo.","evidence":"Superresolution live imaging with KO/rescue/mutagenesis; co-IP with proinsulin and Sec12; proteoglycan competition; conditional liver KO and acute depletion mice with lipid/PCSK9 readouts","pmids":["35051356","35562580","35271396","36193893"],"confidence":"High","gaps":["Hepatic PCSK9 dependence differed between models","Structural mechanism of t-ERGIC biogenesis unresolved"]},{"year":2023,"claim":"Generalized SURF4's cargo scope by unbiased proteomics, revealed an ERAD retrotranslocation role with derlins, and extended physiological function to intestinal lipoprotein secretion.","evidence":"Mass spectrometry of KO conditioned media/lysates; CRISPR/co-IP/ubiquitylation epistasis with derlin-1/2, p97 and COX-2; intestine-specific KO mice with co-IP","pmids":["37844105","37676109","38042368"],"confidence":"Medium","gaps":["Cargo recognition rules not unified into a single code","ERAD role mechanistically distinct from anterograde function and based on single lab"]},{"year":2024,"claim":"Dissected COPII coupling at paralog resolution and added disease-relevant cargo, showing SURF4 selects specific SEC24 paralogs (plus a TMED10 co-receptor for PCSK9) and routes SAA1 to drive fibrogenic signaling.","evidence":"SEC24 paralog mutant epistasis, lumenal pocket mutagenesis, co-translational binding assays; conditional liver KO with SAA1-TLR2 epistasis in fibrosis model","pmids":["39531033","39105051"],"confidence":"High","gaps":["Structure of cargo-loaded SURF4–SEC24 complex unknown","Determinants of paralog choice not fully defined"]},{"year":2025,"claim":"Identified an upstream negative regulator, showing YIPF5 directly binds SURF4 and restrains its export and ERGIC tubule formation.","evidence":"Co-IP (direct interaction), YIPF5 KO cells, live imaging of ERGIC tubules, kinetic secretion assays (preprint)","pmids":["bio_10.1101_2025.06.11.659036"],"confidence":"Medium","gaps":["Preprint, single lab, not peer-reviewed","Mechanism by which YIPF5 inhibits SURF4 unresolved"]},{"year":null,"claim":"The essential embryonic cargo(es) underlying Surf4 knockout lethality and a unified structural/biochemical code reconciling motif-based and folding-independent cargo recognition remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of SURF4 with bound cargo","No single recognition rule explains the full cargo repertoire","Essential developmental cargo unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2,3,6,12,17]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[3,17]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,4,10]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,3,10,17]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,10,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,6,12,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,13,15]}],"complexes":[],"partners":["SEC24A","SEC24C","TMED10","SEC12","ERGIC-53","YIPF5","STIM1","DERL2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15260","full_name":"Surfeit locus protein 4","aliases":[],"length_aa":269,"mass_kda":30.4,"function":"Endoplasmic reticulum cargo receptor that mediates the export of lipoproteins by recruiting cargos into COPII vesicles to facilitate their secretion (PubMed:29643117, PubMed:30251625, PubMed:33186557). Acts as a cargo receptor for lipoproteins bearing both APOB and APOA1, thereby regulating lipoprotein delivery and the maintenance of lipid homeostasis (PubMed:29643117, PubMed:33186557). Synergizes with the GTPase SAR1B to mediate transport of circulating lipoproteins (PubMed:33186557). Promotes the secretion of PCSK9 (PubMed:30251625). Also mediates the efficient secretion of erythropoietin (EPO) (PubMed:32989016). May also play a role in the maintenance of the architecture of the endoplasmic reticulum-Golgi intermediate compartment and of the Golgi (PubMed:18287528)","subcellular_location":"Endoplasmic reticulum membrane; Endoplasmic reticulum-Golgi intermediate compartment membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/O15260/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SURF4","classification":"Not Classified","n_dependent_lines":129,"n_total_lines":1208,"dependency_fraction":0.10678807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPB2","stoichiometry":0.2},{"gene":"STX6","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2},{"gene":"TMED2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SURF4","total_profiled":1310},"omim":[{"mim_id":"620847","title":"BONE MORPHOGENETIC PROTEIN 8A; BMP8A","url":"https://www.omim.org/entry/620847"},{"mim_id":"620436","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 9; TMED9","url":"https://www.omim.org/entry/620436"},{"mim_id":"601924","title":"COATOMER PROTEIN COMPLEX, SUBUNIT ALPHA; COPA","url":"https://www.omim.org/entry/601924"},{"mim_id":"601567","title":"LECTIN, MANNOSE-BINDING 1; LMAN1","url":"https://www.omim.org/entry/601567"},{"mim_id":"185660","title":"SURFEIT 4; SURF4","url":"https://www.omim.org/entry/185660"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SURF4"},"hgnc":{"alias_symbol":["ERV29","FLJ22993","MGC102753"],"prev_symbol":[]},"alphafold":{"accession":"O15260","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15260","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15260-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15260-F1-predicted_aligned_error_v6.png","plddt_mean":84.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SURF4","jax_strain_url":"https://www.jax.org/strain/search?query=SURF4"},"sequence":{"accession":"O15260","fasta_url":"https://rest.uniprot.org/uniprotkb/O15260.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15260/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15260"}},"corpus_meta":[{"pmid":"18287528","id":"PMC_18287528","title":"The cargo receptors Surf4, endoplasmic reticulum-Golgi intermediate compartment (ERGIC)-53, and p25 are required to maintain the architecture of ERGIC and Golgi.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18287528","citation_count":98,"is_preprint":false},{"pmid":"30251625","id":"PMC_30251625","title":"The cargo receptor SURF4 promotes the efficient cellular secretion of PCSK9.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30251625","citation_count":80,"is_preprint":false},{"pmid":"30086131","id":"PMC_30086131","title":"Surf4 (Erv29p) binds amino-terminal tripeptide motifs of soluble cargo proteins with different affinities, enabling prioritization of their exit from the endoplasmic reticulum.","date":"2018","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/30086131","citation_count":57,"is_preprint":false},{"pmid":"29643117","id":"PMC_29643117","title":"SFT-4/Surf4 control ER export of soluble cargo proteins and participate in ER exit site organization.","date":"2018","source":"The Journal of cell 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chimeras.\",\n      \"method\": \"In vitro translation, salt/detergent extraction, proteolysis protection assay, immunofluorescence of myc-tagged Surf4 transfectants\",\n      \"journal\": \"Molecular membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical fractionation and proteolysis protection with immunofluorescence confirmation in one study, single lab\",\n      \"pmids\": [\"7540914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SURF4 physically interacts with ERGIC-53 and p24 proteins in the early secretory pathway. Co-silencing SURF4 with ERGIC-53, or silencing the p24 family member p25, causes reduced ERGIC cluster number and Golgi fragmentation, partial redistribution of COPI (but not Golgi matrix proteins) to the cytosol, and partial brefeldin-A resistance of the cis-Golgi—without blocking anterograde transport. Live imaging showed decreased ERGIC cluster stability after p25 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, live-cell imaging, immunofluorescence, brefeldin A treatment\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction plus functional epistasis with multiple knockdown conditions and live imaging, replicated across multiple perturbations in one rigorous study\",\n      \"pmids\": [\"18287528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SURF4 is the primary ER cargo receptor mediating efficient secretion of PCSK9 in HEK293T cells. SURF4 localizes to the early secretory pathway, physically interacts with PCSK9, and its deletion causes ER accumulation and reduced extracellular secretion of PCSK9, rescued by SURF4 cDNA re-expression.\",\n      \"method\": \"Proximity-dependent biotinylation (BioID) proteomics, genome-scale CRISPR screen, multiple independent sgRNAs, clonal SURF4-deficient cell lines, functional rescue with SURF4 cDNA, co-immunoprecipitation, subcellular fractionation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (BioID, CRISPR screen, co-IP, rescue) in a single rigorous study\",\n      \"pmids\": [\"30251625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SURF4 functions as a cargo receptor that binds amino-terminal tripeptide motifs (ER-ESCAPE motifs) exposed after signal sequence cleavage on soluble cargo proteins, enabling their preferential ER export. Binding affinity scales with aggregation propensity of the cargo; single amino acid changes in the tripeptide alter ER retention. Human cells lacking SURF4 lose preferential trafficking of strong ER-ESCAPE motif cargoes; re-expression of SURF4 or yeast Erv29p rescues this.\",\n      \"method\": \"Mutagenesis of N-terminal tripeptide motifs, SURF4 knockout human cells, functional rescue with SURF4 or Erv29p, systematic survey of 8,000 tripeptide variants, secretion assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis across thousands of motif variants combined with KO rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30086131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SFT-4 (C. elegans SURF4 homolog) localizes predominantly to ER exit sites (ERES) and physically interacts with the yolk lipoprotein VIT-2, promoting its ER export. Mammalian SURF4 physically interacts with apolipoprotein B and its loss causes ER accumulation of apoB in human hepatic HepG2 cells. Loss of SFT-4/SURF4 also reduces the number of COPII-positive ERES.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, in vivo interaction assay in C. elegans, siRNA knockdown in HepG2 cells, ERES quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal evidence from two organisms, co-IP and localization, functional ERES phenotype confirmed\",\n      \"pmids\": [\"29643117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SURF4 associates with STIM1 in the ER. Deletion of Surf4 in DT40 B cells results in markedly increased store-operated Ca²⁺ entry (SOCE) and facilitated STIM1 clustering upon store depletion, indicating SURF4 negatively modulates STIM1-mediated SOCE.\",\n      \"method\": \"Affinity purification for STIM1-binding proteins, co-immunoprecipitation, Surf4 knockout DT40 B cells, Ca²⁺ entry measurements\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification plus KO functional phenotype in single lab study\",\n      \"pmids\": [\"22609200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SURF4 functions as an ER cargo receptor mediating efficient secretion of erythropoietin (EPO). SURF4 disruption causes intracellular EPO accumulation in the ER and reduced extracellular EPO; SURF4 and EPO physically interact. SURF4 overexpression increases EPO secretion. These findings were confirmed in multiple cell lines including endogenous EPO-secreting Hep3B cells under hypoxia.\",\n      \"method\": \"Genome-scale CRISPR screen, multiple independent sgRNAs, SURF4 cDNA rescue, co-immunoprecipitation, subcellular fractionation/immunofluorescence, endogenous EPO secretion assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus multiple sgRNAs, rescue, co-IP, subcellular fractionation, confirmed in endogenous system\",\n      \"pmids\": [\"32989016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Homozygous Surf4 knockout mice are embryonic lethal (between E3.5 and E9.5), demonstrating SURF4 is essential for early embryonic development in vivo, and implying additional essential cargoes or functions beyond known ones.\",\n      \"method\": \"CRISPR/Cas9 germline knockout mice, embryonic staging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined embryonic lethal phenotype, single lab\",\n      \"pmids\": [\"31978056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Progranulin interacts with prosaposin in the ER lumen; prosaposin physically interacts with SURF4, and SURF4 is critical for efficient ER exit of both progranulin and prosaposin. Thus SURF4 mediates lysosomal delivery of progranulin via a prosaposin relay.\",\n      \"method\": \"Co-immunoprecipitation, SURF4 knockdown/knockout, subcellular fractionation, secretion assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus KD/KO phenotype in single lab study\",\n      \"pmids\": [\"34919127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hepatic liver-specific Surf4 knockout mice show no effect on PCSK9 secretion (negative finding for this model), but a significant reduction in plasma cholesterol, triglycerides, and apoB due to impaired VLDL secretion. Surf4 co-immunoprecipitates and colocalizes with apolipoprotein B100 in human hepatocytes. Knockdown of hepatic Surf4 in Ldlr-/- mice reduces atherosclerosis without causing liver lipid accumulation.\",\n      \"method\": \"Liver-specific Surf4 knockout mice, co-immunoprecipitation, immunofluorescence colocalization, siRNA knockdown, lipid measurements, atherosclerosis quantification\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO confirmed by co-IP and colocalization plus atherosclerosis readout; consistent with parallel studies\",\n      \"pmids\": [\"34118252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SURF4 induces a distinct tubular ERGIC (t-ERGIC) that is ERGIC-53-negative but Rab1A/B-positive, with high surface-to-volume ratio and fast ER-to-Golgi travel speed. SURF4 recognizes N-terminal signals of soluble cargoes, co-clusters with them to expand the ER exit site, and t-ERGIC biogenesis and cargo selectivity both depend on SURF4. The fast SURF4-dependent transport is antagonized by KDEL-mediated ER retrieval.\",\n      \"method\": \"Live-cell superresolution imaging, SURF4 KO/knockdown, SURF4 rescue, N-terminal signal mutagenesis, trafficking kinetics assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging with superresolution plus KO/rescue and mutagenesis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35051356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SURF4 facilitates ER export of Sonic Hedgehog (Shh) via an ER export signal, and proteoglycans promote dissociation of SURF4 from Shh at the Golgi, constituting a SURF4-to-proteoglycan relay mechanism for Shh secretion.\",\n      \"method\": \"Co-immunoprecipitation, ER export signal mutagenesis, proteoglycan competition assays, subcellular fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus mutagenesis and Golgi dissociation assay, single lab study\",\n      \"pmids\": [\"35271396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Surf4 promotes ER export of proinsulin in pancreatic β-cells by recruiting proinsulin to ERES. Surf4 expression is upregulated under high-glucose conditions. Surf4 forms oligomers and physically interacts with both proinsulin and Sec12 (essential for COPII vesicle formation), suggesting it delivers proinsulin into COPII vesicles cooperatively with Sec12. Surf4 knockdown causes proinsulin ER retention and decreased mature insulin and insulin secretion.\",\n      \"method\": \"Surf4 knockdown, co-immunoprecipitation with proinsulin and Sec12, immunofluorescence colocalization at ERES, insulin secretion assays, oligomerization assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP with two binding partners plus KD phenotype and ERES localization, multiple orthogonal methods\",\n      \"pmids\": [\"35562580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hepatic Surf4-conditional knockout mice show ~60% reduction in plasma PCSK9, ~50% increase in hepatic LDLR, and a severe defect in hepatic lipoprotein secretion (APOB-containing lipoproteins), causing marked reduction in plasma cholesterol and triglycerides. Acute depletion by liver-targeted CRISPR/Cas9 or siRNA confirms these findings in vivo.\",\n      \"method\": \"Conditional KO mice (Surf4 Alb-Cre), acute CRISPR/Cas9 and siRNA depletion in adult mice, plasma PCSK9/LDLR/lipid measurements, lipoprotein metabolism characterization\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO confirmed by two orthogonal acute depletion methods, replicated across models\",\n      \"pmids\": [\"36193893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SURF4 traffics a broad range of secretory cargoes in HuH7 hepatocytes, as identified by mass spectrometry of conditioned media and cell lysates from SURF4 CRISPR knockout cells. Cargo recognition is governed by complex mechanisms rather than a universal binding motif.\",\n      \"method\": \"CRISPR gene inactivation, mass spectrometry of conditioned media and cell lysates\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic proteomics of KO cells, single lab study\",\n      \"pmids\": [\"37844105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intestinal Surf4 is essential for apolipoprotein (ApoA1, ApoB48, PRAP1) transport and chylomicron/HDL secretion. Intestine-specific Surf4 KO mice display ectopic lipid deposition in the small intestine and hypolipidemia. Surf4 co-localizes with apoB and co-immunoprecipitates with apoB48 in differentiated Caco-2 cells.\",\n      \"method\": \"Intestine-specific KO mice, co-immunoprecipitation, immunofluorescence colocalization, proteomics, lipid measurements\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo intestinal KO with co-IP and colocalization in cell model, multiple orthogonal methods\",\n      \"pmids\": [\"38042368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Surf4 collaborates with derlin-2 and derlin-1 in ERAD: Surf4 acts downstream of derlin-2 and derlin-1 to mediate COX-2 translocation from the ER lumen to the cytosol. Surf4 knockdown impedes COX-2 ubiquitylation and its interaction with caveolin-1 and p97 in the cytosol. Surf4 and p97 preferentially interact with non-glycosylated COX-2.\",\n      \"method\": \"CRISPR library screen, siRNA knockdown, co-immunoprecipitation, ubiquitylation assays, N-glycosylation mutant analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus co-IP and knockdown epistasis, single lab study\",\n      \"pmids\": [\"37676109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SURF4 recruits different SEC24 paralogs of the COPII coat for export of different cargoes: PCSK9 requires both SURF4 and co-receptor TMED10 for export via SEC24A, whereas Cab45 and NUCB1 require SEC24C/D. ER export signals of Cab45 and NUCB1 bind co-translationally to a lumenal pocket of SURF4, contrasting models requiring cargo folding before receptor engagement.\",\n      \"method\": \"Epistasis using SEC24 paralog-specific mutants, co-immunoprecipitation with TMED10, mutagenesis of lumenal SURF4 pocket, co-translational binding assays, secretion assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of receptor pocket, functional dissection of SEC24 paralog usage, co-translational binding assay, multiple cargoes tested\",\n      \"pmids\": [\"39531033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepatic SURF4 facilitates SAA1 (serum amyloid A1) secretion. SURF4 co-immunoprecipitates and colocalizes with SAA1. Surf4 liver-specific KO reduces SAA1 secretion from hepatocytes, decreasing hepatic stellate cell (HSC) activation (via SAA1-TLR2 signaling) and attenuating liver fibrosis.\",\n      \"method\": \"Conditional Surf4 KO mice, co-immunoprecipitation, colocalization, conditioned medium assays, SAA1 knockdown epistasis, TLR2 knockdown in LX-2 cells, CCl4-fibrosis model\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with co-IP plus epistasis knockdown experiments confirming SAA1-TLR2 pathway, multiple orthogonal methods\",\n      \"pmids\": [\"39105051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Surf4 facilitates somatic cell reprogramming to iPSCs by activating the ER stress response (UPR) at an early stage of reprogramming. Surf4 co-expressed with OSKM activates Hspa5 and spliced Xbp1; blocking UPR compromises Surf4's reprogramming effect.\",\n      \"method\": \"Secondary reprogramming system, RNA-seq, qPCR, Western blot, alkaline phosphatase staining, UPR inhibition experiments\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KO/OE with transcriptomic validation and UPR inhibition rescue, but indirect pathway placement, single lab\",\n      \"pmids\": [\"34585448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YIPF5 directly interacts with SURF4 and negatively regulates SURF4-mediated ER export. YIPF5 depletion alters SURF4 localization, causing elongated ERGIC53- and Rab1-positive tubules from COPII-labeled ER exit sites, and kinetic analysis shows enhanced SURF4-mediated ER export in YIPF5 KO cells.\",\n      \"method\": \"Co-immunoprecipitation (direct interaction), YIPF5 KO cells, live-cell imaging of ERGIC tubules, kinetic secretion assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus KO imaging and kinetic assays, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.06.11.659036\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SURF4 is a polytopic ER-resident transmembrane cargo receptor that selectively captures soluble secretory proteins bearing N-terminal tripeptide ER-ESCAPE motifs via a lumenal binding pocket (engaging cargoes co-translationally), recruits them into COPII-coated vesicles by engaging specific SEC24 paralogs (SEC24A for PCSK9/TMED10 co-receptor pathway; SEC24C/D for Cab45/NUCB1), drives formation of a tubular ERGIC that accelerates ER-to-Golgi transport, physically interacts with ERGIC-53 and p24 proteins to maintain ERGIC/Golgi architecture via COPI recruitment, mediates secretion of a broad cargo repertoire including PCSK9, apolipoprotein B, EPO, proinsulin, progranulin/prosaposin, SAA1, and Shh, and also participates in ERAD by cooperating with derlin-2/derlin-1 to retrotranslocate COX-2 to the cytosol; additionally, SURF4 negatively modulates STIM1-dependent store-operated Ca²⁺ entry and is negatively regulated by YIPF5.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SURF4 is an ER-resident polytopic transmembrane cargo receptor that selectively captures soluble secretory proteins and delivers them into the COPII-dependent ER-to-Golgi pathway [#0, #2, #3]. It recognizes cargo through N-terminal tripeptide ER-ESCAPE motifs exposed after signal-sequence cleavage, with binding affinity scaling to cargo aggregation propensity and single residue changes altering ER retention [#3]; ER export signals can engage a lumenal SURF4 pocket co-translationally rather than requiring prior cargo folding [#17]. SURF4 co-clusters with bound cargo to expand ER exit sites and nucleates a distinct tubular ERGIC (ERGIC-53-negative, Rab1A/B-positive) that accelerates ER-to-Golgi transport, a process antagonized by KDEL-mediated retrieval [#10]. Cargo is loaded into COPII vesicles via paralog-selective SEC24 engagement and accessory factors, including a TMED10 co-receptor route for PCSK9 [#17, #12]. Through this machinery SURF4 mediates secretion of a broad cargo repertoire — PCSK9, apolipoprotein B and VLDL/chylomicron lipoproteins, erythropoietin, proinsulin, the progranulin/prosaposin pair, Sonic Hedgehog, and SAA1 — with cargo recognition governed by complex determinants beyond a single universal motif [#2, #4, #6, #8, #9, #11, #12, #14, #15, #18]. SURF4 also functions in the ERGIC/Golgi architecture maintenance via interactions with ERGIC-53 and p24 proteins and COPI recruitment [#1], cooperates with derlin-2/derlin-1 to retrotranslocate COX-2 during ERAD [#16], and negatively modulates STIM1-dependent store-operated Ca²⁺ entry [#5]. SURF4-mediated export is negatively regulated by direct binding of YIPF5 [#20]. Loss of Surf4 is embryonic lethal in mice, and tissue-specific deletion lowers plasma cholesterol, triglycerides and PCSK9 and attenuates atherosclerosis and liver fibrosis [#7, #9, #13, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the basic identity of SURF4 as an ER membrane protein, defining where in the cell it could act before any function was known.\",\n      \"evidence\": \"In vitro translation, microsomal fractionation, proteolysis protection, and immunofluorescence of myc-tagged chimeras\",\n      \"pmids\": [\"7540914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cargo or pathway function assigned\", \"Transmembrane topology only predicted, not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed SURF4 is not merely ER-resident but a structural participant in early secretory architecture, physically engaging ERGIC-53 and p24 proteins to maintain ERGIC clusters and Golgi integrity.\",\n      \"evidence\": \"Co-IP, siRNA co-silencing, live imaging, and brefeldin A assays in cultured cells\",\n      \"pmids\": [\"18287528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify soluble cargoes\", \"Mechanism of COPI recruitment not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a non-trafficking role by linking SURF4 to ER calcium signaling, showing it restrains STIM1-mediated store-operated Ca²⁺ entry.\",\n      \"evidence\": \"Affinity purification, co-IP, and Ca²⁺ entry measurements in Surf4-knockout DT40 B cells\",\n      \"pmids\": [\"22609200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of STIM1 modulation unresolved\", \"Single cell-type system\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined SURF4 as a selective cargo receptor and decoded its recognition logic — N-terminal ER-ESCAPE tripeptide motifs exposed after signal cleavage — establishing how it discriminates soluble export clients.\",\n      \"evidence\": \"Systematic mutagenesis of ~8,000 tripeptide variants, KO human cells, and rescue with SURF4 or yeast Erv29p; parallel BioID/CRISPR/co-IP studies identifying PCSK9 and apoB/VIT-2 as cargoes\",\n      \"pmids\": [\"30086131\", \"30251625\", \"29643117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of motif binding pocket not resolved\", \"Did not explain cargoes lacking strong motifs\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the cargo repertoire to erythropoietin and demonstrated organismal essentiality, showing SURF4 function is required for early embryonic development.\",\n      \"evidence\": \"Genome-scale CRISPR screen, multiple sgRNAs, rescue, co-IP for EPO; CRISPR/Cas9 germline knockout mice\",\n      \"pmids\": [\"32989016\", \"31978056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Essential embryonic cargo not identified\", \"EPO recognition determinants undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened cargo classes (progranulin via a prosaposin relay) and connected SURF4 to ER stress signaling during cell reprogramming, indicating roles beyond constitutive secretion.\",\n      \"evidence\": \"Co-IP, KD/KO secretion assays for progranulin/prosaposin; reprogramming system with RNA-seq and UPR inhibition\",\n      \"pmids\": [\"34919127\", \"34585448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reprogramming role is indirect pathway placement\", \"How SURF4 activates UPR unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the trafficking machinery in mechanistic and physiological depth — SURF4 nucleates a fast tubular ERGIC, cooperates with Sec12 for proinsulin export, relays Shh to proteoglycans, and drives hepatic lipoprotein secretion in vivo.\",\n      \"evidence\": \"Superresolution live imaging with KO/rescue/mutagenesis; co-IP with proinsulin and Sec12; proteoglycan competition; conditional liver KO and acute depletion mice with lipid/PCSK9 readouts\",\n      \"pmids\": [\"35051356\", \"35562580\", \"35271396\", \"36193893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hepatic PCSK9 dependence differed between models\", \"Structural mechanism of t-ERGIC biogenesis unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generalized SURF4's cargo scope by unbiased proteomics, revealed an ERAD retrotranslocation role with derlins, and extended physiological function to intestinal lipoprotein secretion.\",\n      \"evidence\": \"Mass spectrometry of KO conditioned media/lysates; CRISPR/co-IP/ubiquitylation epistasis with derlin-1/2, p97 and COX-2; intestine-specific KO mice with co-IP\",\n      \"pmids\": [\"37844105\", \"37676109\", \"38042368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo recognition rules not unified into a single code\", \"ERAD role mechanistically distinct from anterograde function and based on single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Dissected COPII coupling at paralog resolution and added disease-relevant cargo, showing SURF4 selects specific SEC24 paralogs (plus a TMED10 co-receptor for PCSK9) and routes SAA1 to drive fibrogenic signaling.\",\n      \"evidence\": \"SEC24 paralog mutant epistasis, lumenal pocket mutagenesis, co-translational binding assays; conditional liver KO with SAA1-TLR2 epistasis in fibrosis model\",\n      \"pmids\": [\"39531033\", \"39105051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of cargo-loaded SURF4–SEC24 complex unknown\", \"Determinants of paralog choice not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an upstream negative regulator, showing YIPF5 directly binds SURF4 and restrains its export and ERGIC tubule formation.\",\n      \"evidence\": \"Co-IP (direct interaction), YIPF5 KO cells, live imaging of ERGIC tubules, kinetic secretion assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.11.659036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, not peer-reviewed\", \"Mechanism by which YIPF5 inhibits SURF4 unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The essential embryonic cargo(es) underlying Surf4 knockout lethality and a unified structural/biochemical code reconciling motif-based and folding-independent cargo recognition remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of SURF4 with bound cargo\", \"No single recognition rule explains the full cargo repertoire\", \"Essential developmental cargo unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2, 3, 6, 12, 17]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [3, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 4, 10]},\n      {\"term_id\": \"GO:0005793\", \"supporting_discovery_ids\": [1, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3, 10, 17]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 10, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 6, 12, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 13, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SEC24A\", \"SEC24C\", \"TMED10\", \"SEC12\", \"ERGIC-53\", \"YIPF5\", \"STIM1\", \"DERL2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}