{"gene":"CCPG1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2017,"finding":"CCPG1 is an ER-resident transmembrane protein that functions as a non-canonical autophagy cargo receptor for ER-phagy (reticulophagy). It directly binds to ATG8-family proteins (LC3, GABARAP) via an LIR motif, and independently and via a discrete motif binds to FIP200/RB1CC1. Both interactions are required for its function as a reticulophagy receptor. CCPG1 transcription is induced by the unfolded protein response, directly linking ER stress to ER-phagy. In vivo, CCPG1 loss causes ER luminal protein aggregation, UPR hyperactivation, and exocrine pancreas tissue injury.","method":"Co-immunoprecipitation, motif mutagenesis, in vivo mouse knockout with histological and biochemical readouts, UPR reporter assays","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with motif mutagenesis, in vivo KO with defined phenotype, replicated across multiple follow-up studies","pmids":["29290589","29916296","30263939"],"is_preprint":false},{"year":2006,"finding":"CCPG1 (originally identified as a scaffold protein) binds to the DH/PH domain tandem of the RhoGEF Dbs and inhibits Dbs exchange activity toward RhoA but not Cdc42, thereby restricting substrate utilization of this promiscuous RhoGEF. The isolated Dbs-binding domain of CCPG1 was not sufficient to suppress RhoA exchange activity, indicating a regulatory (not merely tethering) interaction. CCPG1 also recruits endogenous Src kinase into Dbs-containing complexes and interacts with Cdc42.","method":"Co-immunoprecipitation, GEF activity assays in mammalian cells, siRNA knockdown of endogenous CCPG1, domain truncation experiments","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional GEF assay and knockdown, single lab","pmids":["17000758"],"is_preprint":false},{"year":2023,"finding":"The ER luminal region of CCPG1 contains several highly conserved cargo-interacting regions (CIRs) that directly interact with specific ER luminal cargo proteins for ER-phagy. The aggregation-prone 6xIAPP and the endogenous cargo P3H4 bind to different CIRs, establishing CCPG1 as a bispecific ER-phagy receptor that bridges ER luminal cargo recognition with the autophagosomal membrane machinery.","method":"In vitro binding assays, pulldown experiments with truncation/deletion mutants of CCPG1 luminal region, cell-based degradation assays with 6xIAPP and P3H4 as substrates","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding assays with defined domain mutants plus functional degradation readouts, single lab with multiple orthogonal approaches","pmids":["36735498","40395301"],"is_preprint":false},{"year":2023,"finding":"In granulosa cells, ER stress activates reticulophagy through an ATF4–MAP1LC3A–CCPG1 pathway. ATF4 transcriptionally targets MAP1LC3A, and MAP1LC3A physically interacts with CCPG1 (demonstrated by Co-IP). CCPG1 knockdown shifts granulosa cell death from apoptosis to necroptosis mediated via STAT1/STAT3-(p)RIPK1-(p)RIPK3-(p)MLKL, impairing ER proteostasis.","method":"RNAi knockdown of ATF4 and CCPG1, ChIP-seq (ATF4 at MAP1LC3A promoter), co-immunoprecipitation (MAP1LC3A–CCPG1 interaction), cell death assays","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP-seq plus RNAi phenotypic readouts, single lab","pmids":["36769070"],"is_preprint":false},{"year":2025,"finding":"Cisplatin treatment inhibits reticulophagy by downregulating CCPG1 expression through the ATM–CHEK2/Chk2 signaling pathway in bladder cancer cells. Overexpression of wild-type CCPG1, but not an LC3-binding-deficient variant, rescues reticulophagy and promotes tumor growth, establishing that the LC3-interaction of CCPG1 is functionally required for its pro-tumorigenic reticulophagy activity.","method":"CCPG1 knockdown and overexpression (wild-type vs. LC3-binding-deficient mutant), pharmacological inhibition of ATM-CHEK2 pathway, reticulophagy flux assays, cell proliferation and apoptosis assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LIR-motif mutagenesis with functional rescue, pathway inhibitor experiments, single lab","pmids":["41361995"],"is_preprint":false},{"year":2025,"finding":"In KRAS-driven pancreatic oncogenesis, ER-phagy failure causes pathologic aggregation of a subset of ER luminal proteins, including REG3B, due to failure to physically interact with the ER-phagy receptor CCPG1. Engineered REG3B mutants that cannot bind CCPG1 and form aggregates are sufficient to drive acinar-ductal metaplasia-primed epithelial cell states, placing CCPG1 upstream of proteostatic control of pre-malignant transformation.","method":"Proteomics, high-resolution imaging, spatial transcriptomics, genetically engineered CCPG1-deficient mice, REG3B interaction mutants","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, imaging, genetic mouse models, engineered mutants), preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"The pathogenic R519Q GluN2B NMDAR variant retained in the ER is recognized by the ER-phagy receptor CCPG1 (along with RTN3L) for autophagic clearance via the lysosomal pathway.","method":"Pharmacological and genetic autophagy inhibition, LIR-motif disruption of GluN2B, co-localization and interaction assays with CCPG1 and RTN3L","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/co-localization, preprint, CCPG1 role is secondary finding in a paper primarily about GluN2B","pmids":[],"is_preprint":true}],"current_model":"CCPG1 is an ER-resident transmembrane protein that functions as a non-canonical reticulophagy (ER-phagy) cargo receptor by simultaneously engaging ATG8-family proteins (via an LIR motif) and FIP200/RB1CC1 (via a discrete FIR motif) on the cytoplasmic side, while its ER luminal cargo-interacting regions (CIRs) directly recognize and capture aberrant ER luminal proteins (such as aggregation-prone 6xIAPP and endogenous P3H4) for autophagic degradation; CCPG1 transcription is induced downstream of ER stress (via ATF4 and the UPR), and in vivo its loss causes ER luminal protein aggregation, UPR hyperactivation, and exocrine pancreatic injury, while an earlier-characterized function as a scaffold that inhibits RhoA-specific GEF activity of Dbs and recruits Src into RhoGEF complexes may reflect a distinct, context-dependent role."},"narrative":{"mechanistic_narrative":"CCPG1 is an endoplasmic reticulum-resident transmembrane protein that serves as a non-canonical cargo receptor for selective autophagy of the ER (reticulophagy/ER-phagy), coupling ER proteostasis to the autophagosomal machinery [PMID:29290589, PMID:29916296, PMID:30263939]. On its cytoplasmic face, CCPG1 directly engages ATG8-family proteins (LC3, GABARAP) through an LIR motif and independently binds FIP200/RB1CC1 through a discrete motif, with both interactions required for receptor function [PMID:29290589, PMID:29916296, PMID:30263939]. Within the ER lumen, CCPG1 bears multiple conserved cargo-interacting regions (CIRs) that directly capture distinct aberrant or aggregation-prone luminal proteins—different CIRs binding the aggregation-prone 6xIAPP and the endogenous cargo P3H4—establishing CCPG1 as a bispecific receptor that bridges luminal cargo recognition to autophagic degradation [PMID:36735498, PMID:40395301]. CCPG1 expression is induced downstream of ER stress via the unfolded protein response and the ATF4 axis, providing a feedback link from ER stress to ER-phagy [PMID:29290589, PMID:29916296, PMID:30263939, PMID:36769070]; in vivo its loss causes ER luminal protein aggregation, UPR hyperactivation, and exocrine pancreas injury [PMID:29290589, PMID:29916296, PMID:30263939]. Through this proteostatic surveillance, CCPG1 governs cell fate decisions in disease contexts, restraining aggregation of luminal proteins such as REG3B during KRAS-driven pancreatic pre-malignant transformation and supporting reticulophagy-dependent tumor growth in bladder cancer, where its LC3 interaction is functionally required [PMID:41361995]. An earlier-characterized role as a scaffold that binds the RhoGEF Dbs to inhibit its RhoA-specific exchange activity and recruits Src into RhoGEF complexes [PMID:17000758] reflects a distinct, context-dependent function not yet integrated with its reticulophagy activity.","teleology":[{"year":2006,"claim":"Before any autophagy role was known, the question was what cellular activity CCPG1 carried; this established it as a scaffold that constrains the substrate specificity of a promiscuous RhoGEF.","evidence":"Co-IP, GEF activity assays, siRNA knockdown, and domain truncations in mammalian cells","pmids":["17000758"],"confidence":"Medium","gaps":["Single lab; not reconciled with the later-defined ER-phagy function","No structural basis for selective inhibition of RhoA versus Cdc42 exchange","Functional significance of Src recruitment to Dbs complexes unresolved"]},{"year":2017,"claim":"The central question of CCPG1's physiological function was answered by defining it as a non-canonical ER-phagy cargo receptor that links ER stress to autophagic clearance and is required to protect tissue.","evidence":"Reciprocal Co-IP with LIR/FIP200-motif mutagenesis, UPR reporter assays, and an in vivo mouse knockout with histological and biochemical readouts","pmids":["29290589","29916296","30263939"],"confidence":"High","gaps":["Did not identify the ER luminal cargoes captured by CCPG1","Structural basis of dual ATG8/FIP200 engagement not resolved","Mechanism coupling UPR transcriptional induction to receptor activity not detailed"]},{"year":2023,"claim":"How CCPG1 selects luminal cargo was unknown; mapping conserved cargo-interacting regions established it as a bispecific receptor that recognizes distinct luminal substrates directly.","evidence":"In vitro binding and pulldown assays with luminal-region truncation/deletion mutants plus cell-based degradation assays using 6xIAPP and P3H4","pmids":["36735498","40395301"],"confidence":"High","gaps":["Full repertoire of endogenous luminal cargoes beyond P3H4 undefined","Structural determinants of CIR-cargo specificity not solved"]},{"year":2023,"claim":"The transcriptional wiring of CCPG1-mediated reticulophagy was clarified by placing it downstream of an ATF4–MAP1LC3A axis that governs cell death mode under ER stress.","evidence":"RNAi of ATF4 and CCPG1, ChIP-seq for ATF4 at the MAP1LC3A promoter, Co-IP of MAP1LC3A–CCPG1, and cell death assays in granulosa cells","pmids":["36769070"],"confidence":"Medium","gaps":["Single lab and single cell type","Direct link between CCPG1 loss and the STAT1/STAT3-RIPK necroptosis switch is correlative"]},{"year":2025,"claim":"Whether CCPG1 reticulophagy is regulated and functionally consequential in cancer was tested, showing CCPG1 is suppressed via ATM–CHEK2 signaling and that its LC3 interaction drives pro-tumorigenic reticulophagy.","evidence":"Knockdown/overexpression of wild-type versus LC3-binding-deficient CCPG1, ATM-CHEK2 pathway inhibition, reticulophagy flux, and proliferation/apoptosis assays in bladder cancer cells","pmids":["41361995"],"confidence":"Medium","gaps":["Single lab; in vivo tumor relevance not established","Direct biochemical link from CHEK2 to CCPG1 transcription not defined"]},{"year":2025,"claim":"The disease relevance of CCPG1 cargo recognition was extended by showing that failure to capture specific luminal proteins drives pre-malignant epithelial states.","evidence":"Proteomics, high-resolution imaging, spatial transcriptomics, CCPG1-deficient mice, and engineered REG3B interaction mutants (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Causal contribution of CCPG1 loss versus REG3B aggregation alone needs separation","Generality across luminal cargoes in oncogenesis unknown"]},{"year":2025,"claim":"The cargo range of CCPG1 was probed for ER-retained membrane proteins, implicating it in clearance of a pathogenic NMDAR variant.","evidence":"Pharmacological and genetic autophagy inhibition, LIR-motif disruption, and co-localization/interaction assays with CCPG1 and RTN3L (preprint)","pmids":[],"confidence":"Low","gaps":["Single Co-IP/co-localization without reciprocal validation; preprint","CCPG1 role is a secondary finding in a GluN2B-focused study","Whether CCPG1 directly recognizes the variant or acts redundantly with RTN3L unclear"]},{"year":null,"claim":"How CCPG1's RhoGEF-scaffolding activity relates mechanistically to its ER-phagy receptor function, and what governs its full endogenous cargo repertoire, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the dual cytoplasmic ATG8/FIP200 and luminal CIR architecture","No unified account reconciling the 2006 Dbs/Src scaffold role with reticulophagy","Comprehensive endogenous luminal cargo set undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":["MAP1LC3A","GABARAP","RB1CC1","P3H4","REG3B","DBS","SRC","RTN3L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULG6","full_name":"Cell cycle progression protein 1","aliases":["Cell cycle progression restoration protein 8"],"length_aa":757,"mass_kda":87.3,"function":"Acts as an assembly platform for Rho protein signaling complexes. Limits guanine nucleotide exchange activity of MCF2L toward RHOA, which results in an inhibition of both its transcriptional activation ability and its transforming activity. Does not inhibit activity of MCF2L toward CDC42, or activity of MCF2 toward either RHOA or CDC42 (By similarity). May be involved in cell cycle regulation","subcellular_location":"Cytoplasmic granule membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULG6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCPG1","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":[{"gene":"ATG101","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CCPG1","total_profiled":1310},"omim":[{"mim_id":"611326","title":"CELL CYCLE PROGRESSION 1; CCPG1","url":"https://www.omim.org/entry/611326"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCPG1"},"hgnc":{"alias_symbol":["KIAA1254","CPR8"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULG6","domains":[{"cath_id":"-","chopping":"346-407_415-459_486-531","consensus_level":"medium","plddt":83.3952,"start":346,"end":531},{"cath_id":"-","chopping":"631-733","consensus_level":"high","plddt":81.4405,"start":631,"end":733}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULG6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULG6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULG6-F1-predicted_aligned_error_v6.png","plddt_mean":62.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCPG1","jax_strain_url":"https://www.jax.org/strain/search?query=CCPG1"},"sequence":{"accession":"Q9ULG6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULG6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULG6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULG6"}},"corpus_meta":[{"pmid":"29290589","id":"PMC_29290589","title":"CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis.","date":"2017","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/29290589","citation_count":372,"is_preprint":false},{"pmid":"29247256","id":"PMC_29247256","title":"miR-498 promotes cell proliferation and inhibits cell apoptosis in retinoblastoma by directly targeting CCPG1.","date":"2017","source":"Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/29247256","citation_count":27,"is_preprint":false},{"pmid":"36769070","id":"PMC_36769070","title":"The Activation of Reticulophagy by ER Stress through the ATF4-MAP1LC3A-CCPG1 Pathway in Ovarian Granulosa Cells Is Linked to Apoptosis and Necroptosis.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36769070","citation_count":22,"is_preprint":false},{"pmid":"29916296","id":"PMC_29916296","title":"CCPG1, a cargo receptor required for reticulophagy and endoplasmic reticulum proteostasis.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/29916296","citation_count":21,"is_preprint":false},{"pmid":"36735498","id":"PMC_36735498","title":"CCPG1 recognizes endoplasmic reticulum luminal proteins for selective ER-phagy.","date":"2023","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/36735498","citation_count":20,"is_preprint":false},{"pmid":"17000758","id":"PMC_17000758","title":"Ccpg1, a novel scaffold protein that regulates the activity of the Rho guanine nucleotide exchange factor Dbs.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17000758","citation_count":17,"is_preprint":false},{"pmid":"29911925","id":"PMC_29911925","title":"CCPG1 is a noncanonical autophagy cargo receptor essential for reticulophagy and pancreatic ER proteostasis.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/29911925","citation_count":14,"is_preprint":false},{"pmid":"35963197","id":"PMC_35963197","title":"Piperine alleviates acute pancreatitis: A possible role for FAM134B and CCPG1 dependent ER-phagy.","date":"2022","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35963197","citation_count":14,"is_preprint":false},{"pmid":"30263939","id":"PMC_30263939","title":"CCPG1, an unconventional cargo receptor for ER-phagy, maintains pancreatic acinar cell health.","date":"2018","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30263939","citation_count":14,"is_preprint":false},{"pmid":"36925093","id":"PMC_36925093","title":"Sodium arsenite-induced cytotoxicity is regulated by BNIP3L/Nix-mediated endoplasmic reticulum stress responses and CCPG1-mediated endoplasmic reticulum-phagy.","date":"2023","source":"Environmental toxicology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36925093","citation_count":3,"is_preprint":false},{"pmid":"35450172","id":"PMC_35450172","title":"CCPG1 involved in corneal Aspergillus fumigatus infection.","date":"2022","source":"International journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/35450172","citation_count":2,"is_preprint":false},{"pmid":"41361995","id":"PMC_41361995","title":"CCPG1-mediated reticulophagy promotes tumorigenesis and cisplatin resistance in bladder cancer.","date":"2025","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41361995","citation_count":1,"is_preprint":false},{"pmid":"40395301","id":"PMC_40395301","title":"Cargo-interacting regions (CIR) of CCPG1 capture ER luminal cargos for reticulophagy.","date":"2023","source":"Autophagy reports","url":"https://pubmed.ncbi.nlm.nih.gov/40395301","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.24.690135","title":"AKT1-phosphorylated TERT assembles a FOXO3-MYC transcriptional complex that drives ERphagy and proteostasis in post-mitotic RPE","date":"2025-11-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.24.690135","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.24.644918","title":"Dysproteostasis primes pancreatic epithelial state changes in  <i>KRAS</i>  -mediated oncogenesis","date":"2025-03-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.24.644918","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.12.632651","title":"A GluN2B disease-associated variant promotes degradation of NMDA receptors via autophagy","date":"2025-01-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.12.632651","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9722,"output_tokens":2278,"usd":0.031668,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9259,"output_tokens":3176,"usd":0.062848,"stage2_stop_reason":"end_turn"},"total_usd":0.094516,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"CCPG1 is an ER-resident transmembrane protein that functions as a non-canonical autophagy cargo receptor for ER-phagy (reticulophagy). It directly binds to ATG8-family proteins (LC3, GABARAP) via an LIR motif, and independently and via a discrete motif binds to FIP200/RB1CC1. Both interactions are required for its function as a reticulophagy receptor. CCPG1 transcription is induced by the unfolded protein response, directly linking ER stress to ER-phagy. In vivo, CCPG1 loss causes ER luminal protein aggregation, UPR hyperactivation, and exocrine pancreas tissue injury.\",\n      \"method\": \"Co-immunoprecipitation, motif mutagenesis, in vivo mouse knockout with histological and biochemical readouts, UPR reporter assays\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with motif mutagenesis, in vivo KO with defined phenotype, replicated across multiple follow-up studies\",\n      \"pmids\": [\"29290589\", \"29916296\", \"30263939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CCPG1 (originally identified as a scaffold protein) binds to the DH/PH domain tandem of the RhoGEF Dbs and inhibits Dbs exchange activity toward RhoA but not Cdc42, thereby restricting substrate utilization of this promiscuous RhoGEF. The isolated Dbs-binding domain of CCPG1 was not sufficient to suppress RhoA exchange activity, indicating a regulatory (not merely tethering) interaction. CCPG1 also recruits endogenous Src kinase into Dbs-containing complexes and interacts with Cdc42.\",\n      \"method\": \"Co-immunoprecipitation, GEF activity assays in mammalian cells, siRNA knockdown of endogenous CCPG1, domain truncation experiments\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional GEF assay and knockdown, single lab\",\n      \"pmids\": [\"17000758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The ER luminal region of CCPG1 contains several highly conserved cargo-interacting regions (CIRs) that directly interact with specific ER luminal cargo proteins for ER-phagy. The aggregation-prone 6xIAPP and the endogenous cargo P3H4 bind to different CIRs, establishing CCPG1 as a bispecific ER-phagy receptor that bridges ER luminal cargo recognition with the autophagosomal membrane machinery.\",\n      \"method\": \"In vitro binding assays, pulldown experiments with truncation/deletion mutants of CCPG1 luminal region, cell-based degradation assays with 6xIAPP and P3H4 as substrates\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding assays with defined domain mutants plus functional degradation readouts, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"36735498\", \"40395301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In granulosa cells, ER stress activates reticulophagy through an ATF4–MAP1LC3A–CCPG1 pathway. ATF4 transcriptionally targets MAP1LC3A, and MAP1LC3A physically interacts with CCPG1 (demonstrated by Co-IP). CCPG1 knockdown shifts granulosa cell death from apoptosis to necroptosis mediated via STAT1/STAT3-(p)RIPK1-(p)RIPK3-(p)MLKL, impairing ER proteostasis.\",\n      \"method\": \"RNAi knockdown of ATF4 and CCPG1, ChIP-seq (ATF4 at MAP1LC3A promoter), co-immunoprecipitation (MAP1LC3A–CCPG1 interaction), cell death assays\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP-seq plus RNAi phenotypic readouts, single lab\",\n      \"pmids\": [\"36769070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cisplatin treatment inhibits reticulophagy by downregulating CCPG1 expression through the ATM–CHEK2/Chk2 signaling pathway in bladder cancer cells. Overexpression of wild-type CCPG1, but not an LC3-binding-deficient variant, rescues reticulophagy and promotes tumor growth, establishing that the LC3-interaction of CCPG1 is functionally required for its pro-tumorigenic reticulophagy activity.\",\n      \"method\": \"CCPG1 knockdown and overexpression (wild-type vs. LC3-binding-deficient mutant), pharmacological inhibition of ATM-CHEK2 pathway, reticulophagy flux assays, cell proliferation and apoptosis assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LIR-motif mutagenesis with functional rescue, pathway inhibitor experiments, single lab\",\n      \"pmids\": [\"41361995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In KRAS-driven pancreatic oncogenesis, ER-phagy failure causes pathologic aggregation of a subset of ER luminal proteins, including REG3B, due to failure to physically interact with the ER-phagy receptor CCPG1. Engineered REG3B mutants that cannot bind CCPG1 and form aggregates are sufficient to drive acinar-ductal metaplasia-primed epithelial cell states, placing CCPG1 upstream of proteostatic control of pre-malignant transformation.\",\n      \"method\": \"Proteomics, high-resolution imaging, spatial transcriptomics, genetically engineered CCPG1-deficient mice, REG3B interaction mutants\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, imaging, genetic mouse models, engineered mutants), preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The pathogenic R519Q GluN2B NMDAR variant retained in the ER is recognized by the ER-phagy receptor CCPG1 (along with RTN3L) for autophagic clearance via the lysosomal pathway.\",\n      \"method\": \"Pharmacological and genetic autophagy inhibition, LIR-motif disruption of GluN2B, co-localization and interaction assays with CCPG1 and RTN3L\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/co-localization, preprint, CCPG1 role is secondary finding in a paper primarily about GluN2B\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CCPG1 is an ER-resident transmembrane protein that functions as a non-canonical reticulophagy (ER-phagy) cargo receptor by simultaneously engaging ATG8-family proteins (via an LIR motif) and FIP200/RB1CC1 (via a discrete FIR motif) on the cytoplasmic side, while its ER luminal cargo-interacting regions (CIRs) directly recognize and capture aberrant ER luminal proteins (such as aggregation-prone 6xIAPP and endogenous P3H4) for autophagic degradation; CCPG1 transcription is induced downstream of ER stress (via ATF4 and the UPR), and in vivo its loss causes ER luminal protein aggregation, UPR hyperactivation, and exocrine pancreatic injury, while an earlier-characterized function as a scaffold that inhibits RhoA-specific GEF activity of Dbs and recruits Src into RhoGEF complexes may reflect a distinct, context-dependent role.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCPG1 is an endoplasmic reticulum-resident transmembrane protein that serves as a non-canonical cargo receptor for selective autophagy of the ER (reticulophagy/ER-phagy), coupling ER proteostasis to the autophagosomal machinery [#0]. On its cytoplasmic face, CCPG1 directly engages ATG8-family proteins (LC3, GABARAP) through an LIR motif and independently binds FIP200/RB1CC1 through a discrete motif, with both interactions required for receptor function [#0]. Within the ER lumen, CCPG1 bears multiple conserved cargo-interacting regions (CIRs) that directly capture distinct aberrant or aggregation-prone luminal proteins—different CIRs binding the aggregation-prone 6xIAPP and the endogenous cargo P3H4—establishing CCPG1 as a bispecific receptor that bridges luminal cargo recognition to autophagic degradation [#2]. CCPG1 expression is induced downstream of ER stress via the unfolded protein response and the ATF4 axis, providing a feedback link from ER stress to ER-phagy [#0, #3]; in vivo its loss causes ER luminal protein aggregation, UPR hyperactivation, and exocrine pancreas injury [#0]. Through this proteostatic surveillance, CCPG1 governs cell fate decisions in disease contexts, restraining aggregation of luminal proteins such as REG3B during KRAS-driven pancreatic pre-malignant transformation [#5] and supporting reticulophagy-dependent tumor growth in bladder cancer, where its LC3 interaction is functionally required [#4]. An earlier-characterized role as a scaffold that binds the RhoGEF Dbs to inhibit its RhoA-specific exchange activity and recruits Src into RhoGEF complexes [#1] reflects a distinct, context-dependent function not yet integrated with its reticulophagy activity.\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Before any autophagy role was known, the question was what cellular activity CCPG1 carried; this established it as a scaffold that constrains the substrate specificity of a promiscuous RhoGEF.\",\n      \"evidence\": \"Co-IP, GEF activity assays, siRNA knockdown, and domain truncations in mammalian cells\",\n      \"pmids\": [\"17000758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; not reconciled with the later-defined ER-phagy function\",\n        \"No structural basis for selective inhibition of RhoA versus Cdc42 exchange\",\n        \"Functional significance of Src recruitment to Dbs complexes unresolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The central question of CCPG1's physiological function was answered by defining it as a non-canonical ER-phagy cargo receptor that links ER stress to autophagic clearance and is required to protect tissue.\",\n      \"evidence\": \"Reciprocal Co-IP with LIR/FIP200-motif mutagenesis, UPR reporter assays, and an in vivo mouse knockout with histological and biochemical readouts\",\n      \"pmids\": [\"29290589\", \"29916296\", \"30263939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not identify the ER luminal cargoes captured by CCPG1\",\n        \"Structural basis of dual ATG8/FIP200 engagement not resolved\",\n        \"Mechanism coupling UPR transcriptional induction to receptor activity not detailed\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How CCPG1 selects luminal cargo was unknown; mapping conserved cargo-interacting regions established it as a bispecific receptor that recognizes distinct luminal substrates directly.\",\n      \"evidence\": \"In vitro binding and pulldown assays with luminal-region truncation/deletion mutants plus cell-based degradation assays using 6xIAPP and P3H4\",\n      \"pmids\": [\"36735498\", \"40395301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full repertoire of endogenous luminal cargoes beyond P3H4 undefined\",\n        \"Structural determinants of CIR-cargo specificity not solved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The transcriptional wiring of CCPG1-mediated reticulophagy was clarified by placing it downstream of an ATF4–MAP1LC3A axis that governs cell death mode under ER stress.\",\n      \"evidence\": \"RNAi of ATF4 and CCPG1, ChIP-seq for ATF4 at the MAP1LC3A promoter, Co-IP of MAP1LC3A–CCPG1, and cell death assays in granulosa cells\",\n      \"pmids\": [\"36769070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab and single cell type\",\n        \"Direct link between CCPG1 loss and the STAT1/STAT3-RIPK necroptosis switch is correlative\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether CCPG1 reticulophagy is regulated and functionally consequential in cancer was tested, showing CCPG1 is suppressed via ATM–CHEK2 signaling and that its LC3 interaction drives pro-tumorigenic reticulophagy.\",\n      \"evidence\": \"Knockdown/overexpression of wild-type versus LC3-binding-deficient CCPG1, ATM-CHEK2 pathway inhibition, reticulophagy flux, and proliferation/apoptosis assays in bladder cancer cells\",\n      \"pmids\": [\"41361995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; in vivo tumor relevance not established\",\n        \"Direct biochemical link from CHEK2 to CCPG1 transcription not defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The disease relevance of CCPG1 cargo recognition was extended by showing that failure to capture specific luminal proteins drives pre-malignant epithelial states.\",\n      \"evidence\": \"Proteomics, high-resolution imaging, spatial transcriptomics, CCPG1-deficient mice, and engineered REG3B interaction mutants (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed\",\n        \"Causal contribution of CCPG1 loss versus REG3B aggregation alone needs separation\",\n        \"Generality across luminal cargoes in oncogenesis unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The cargo range of CCPG1 was probed for ER-retained membrane proteins, implicating it in clearance of a pathogenic NMDAR variant.\",\n      \"evidence\": \"Pharmacological and genetic autophagy inhibition, LIR-motif disruption, and co-localization/interaction assays with CCPG1 and RTN3L (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single Co-IP/co-localization without reciprocal validation; preprint\",\n        \"CCPG1 role is a secondary finding in a GluN2B-focused study\",\n        \"Whether CCPG1 directly recognizes the variant or acts redundantly with RTN3L unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCPG1's RhoGEF-scaffolding activity relates mechanistically to its ER-phagy receptor function, and what governs its full endogenous cargo repertoire, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the dual cytoplasmic ATG8/FIP200 and luminal CIR architecture\",\n        \"No unified account reconciling the 2006 Dbs/Src scaffold role with reticulophagy\",\n        \"Comprehensive endogenous luminal cargo set undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MAP1LC3A\",\n      \"GABARAP\",\n      \"RB1CC1\",\n      \"P3H4\",\n      \"REG3B\",\n      \"Dbs\",\n      \"Src\",\n      \"RTN3L\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":6,"faith_pct":66.66666666666667}}