{"gene":"TMUB1","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2005,"finding":"TMUB1 (HOPS/Hepatocyte Odd Protein Shuttling) is a shuttling protein that binds elongation factor eEF-1A and interferes with protein synthesis. Its nuclear export is governed by cAMP signaling and mediated via the CRM-1 export receptor. Overexpression strongly reduces cell proliferation.","method":"Regenerating liver cDNA library screen; co-immunoprecipitation with eEF-1A; cAMP/CRM-1 export assays; overexpression in H-35 and 3T3-NIH cells with proliferation readout","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — single lab, multiple orthogonal methods (binding assay, nuclear export assay, functional overexpression), but not independently replicated","pmids":["16014383"],"is_preprint":false},{"year":2008,"finding":"TMUB1 (Tmub1/HOPS) facilitates surface recycling of GluR2-containing AMPA receptors. It is enriched in synaptosomal membranes, co-immunoprecipitates with GluR2 and GRIP from mouse brain, and its knockdown reduces AMPA receptor currents and synaptic surface expression of GluR2 (but not GluR1), while overexpression increases GluR2 surface expression.","method":"RNAi knockdown in neurons with electrophysiological readout; overexpression with surface biotinylation assay; co-immunoprecipitation from mouse brain; recycling assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with multiple orthogonal methods (electrophysiology, co-IP, surface expression, recycling assay)","pmids":["18665261"],"is_preprint":false},{"year":2012,"finding":"TMUB1 (HOPS) directly interacts with nucleophosmin (NPM) and p19(Arf), forming a functionally active trimeric complex. NPM regulates HOPS half-life, while HOPS stabilizes p19(Arf) and controls its nucleolar localization. HOPS knockdown causes centrosome hyperamplification and multinucleated cells; overexpression causes G0/G1 arrest.","method":"Co-immunoprecipitation; protein stability assays; siRNA knockdown with cell cycle and centrosome phenotype readouts; overexpression with cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — single lab, multiple orthogonal methods (co-IP, KD phenotype, OE phenotype, localization)","pmids":["22890319"],"is_preprint":false},{"year":2019,"finding":"TMUB1 (HOPS) retains p53 in the cytoplasm by binding p53, inhibiting its proteasomal degradation, and interfering with importin-α to block nuclear import. This promotes p53 recruitment to mitochondria and induction of the intrinsic apoptosis pathway. Hops−/− mice show significantly reduced apoptosis upon chemotherapeutic challenge.","method":"Hops−/− mouse model; co-immunoprecipitation of HOPS with p53; importin-α interaction assay; mitochondrial fractionation; apoptosis assays in vivo and in cells","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo knockout mouse with defined apoptosis phenotype, co-IP with p53, importin-α competition, mitochondrial recruitment, multiple orthogonal methods in single rigorous study","pmids":["31867855"],"is_preprint":false},{"year":2022,"finding":"TMUB1 modulates PD-L1 post-translational modifications in tumor cells: it competes with the E3 ubiquitin ligase HUWE1 for interaction with PD-L1 and inhibits PD-L1 polyubiquitination at K281 in the endoplasmic reticulum. Additionally, TMUB1 recruits STT3A to enhance PD-L1 N-glycosylation and stability, promoting PD-L1 maturation and tumor immune evasion.","method":"Co-immunoprecipitation of TMUB1 with PD-L1 and HUWE1; ubiquitination assay identifying K281 site; glycosylation assays with STT3A recruitment; TMUB1 knockdown/overexpression with PD-L1 stability and immune evasion readouts; synthetic competing peptide in mouse tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (co-IP, ubiquitination site mapping, glycosylation assay, in vivo peptide competition), single rigorous study with strong mechanistic depth","pmids":["36376293"],"is_preprint":false}],"current_model":"TMUB1 (also called HOPS) is a multifunctional ubiquitin-like domain-containing shuttling protein that: (1) retains cytoplasmic p53 from proteasomal degradation and nuclear import to promote mitochondrial apoptosis; (2) stabilizes PD-L1 by inhibiting HUWE1-mediated polyubiquitination at K281 and recruiting STT3A to enhance N-glycosylation in the ER; (3) facilitates synaptic surface recycling of GluR2-containing AMPA receptors by interacting with GluR2 and GRIP; and (4) bridges NPM and p19(Arf) to regulate cell cycle progression and p19(Arf) nucleolar localization."},"narrative":{"teleology":[{"year":2005,"claim":"Identification of TMUB1 as a nucleocytoplasmic shuttling protein that binds eEF-1A and suppresses proliferation established it as a functionally active signaling intermediary rather than a passive structural component.","evidence":"Regenerating liver cDNA screen; co-IP with eEF-1A; CRM-1 export and cAMP regulation assays; overexpression growth suppression in H-35 and 3T3-NIH cells","pmids":["16014383"],"confidence":"Medium","gaps":["Mechanism by which eEF-1A binding suppresses translation not delineated","Findings from a single lab without independent replication","In vivo relevance of the proliferation-suppressive effect not tested"]},{"year":2008,"claim":"Demonstrating that TMUB1 selectively promotes surface recycling of GluR2-containing AMPA receptors expanded its role to post-synaptic membrane trafficking, answering how GluR2 surface levels are maintained at synapses.","evidence":"RNAi knockdown in neurons with electrophysiology; surface biotinylation; co-IP of TMUB1 with GluR2 and GRIP from mouse brain; recycling assay","pmids":["18665261"],"confidence":"Medium","gaps":["Single-lab study without independent replication","Structural basis of the TMUB1–GluR2–GRIP interaction unknown","Whether TMUB1 functions in long-term synaptic plasticity not tested"]},{"year":2012,"claim":"Discovery of a TMUB1–NPM–p19(Arf) trimeric complex revealed how TMUB1 integrates nucleolar surveillance with cell cycle control, explaining centrosome hyperamplification upon TMUB1 loss.","evidence":"Co-IP; protein stability assays; siRNA knockdown with centrosome and cell cycle phenotypes; overexpression inducing G0/G1 arrest","pmids":["22890319"],"confidence":"Medium","gaps":["Single-lab study; trimeric complex not reconstituted in vitro","Whether TMUB1 loss causes centrosome defects through p19(Arf)-dependent or -independent pathways not resolved","Relevance of the complex to tumorigenesis in vivo not established"]},{"year":2019,"claim":"Using knockout mice, the p53-retention mechanism was resolved: TMUB1 competes with importin-α for p53 binding, blocking nuclear import and channeling p53 to mitochondria to activate intrinsic apoptosis—the first in vivo demonstration of TMUB1 function.","evidence":"Hops−/− mouse model; co-IP of TMUB1 with p53; importin-α competition assay; mitochondrial fractionation; in vivo apoptosis upon chemotherapy","pmids":["31867855"],"confidence":"High","gaps":["Whether TMUB1–p53 interaction is direct or requires bridging factors not structurally resolved","Relative contributions of p53 stabilization versus nuclear import blockade not quantitatively separated","Tumor-suppressive consequences of TMUB1 loss not formally tested in cancer models"]},{"year":2022,"claim":"The PD-L1 stabilization mechanism answered how tumor cells upregulate immune checkpoint ligands post-translationally: TMUB1 outcompetes HUWE1 at K281 to prevent polyubiquitination and recruits STT3A for N-glycosylation, establishing TMUB1 as a targetable node in immune evasion.","evidence":"Co-IP of TMUB1 with PD-L1 and HUWE1; ubiquitination site mapping at K281; glycosylation assay with STT3A; TMUB1 KD/OE with PD-L1 stability readout; competing peptide in mouse tumor models","pmids":["36376293"],"confidence":"High","gaps":["Whether TMUB1-mediated PD-L1 stabilization occurs in all tumor types or is context-dependent","Structural basis of TMUB1 competition with HUWE1 unknown","Whether TMUB1 regulates glycosylation of other ER clients besides PD-L1 not examined"]},{"year":null,"claim":"No structural model of TMUB1 exists, and how a single shuttling protein coordinates such diverse substrates (p53, PD-L1, GluR2, NPM/Arf) through its ubiquitin-like domain and transmembrane segments remains mechanistically unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of TMUB1 or any of its complexes","How substrate selectivity is achieved across ER, cytoplasm, and synaptic compartments unknown","Functional significance of the ubiquitin-like domain not dissected by mutagenesis across all interaction partners"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4]}],"complexes":["NPM–p19(Arf)–TMUB1 trimeric complex"],"partners":["TP53","CD274","HUWE1","STT3A","NPM1","CDKN2A","GRIA2","GRIP1"],"other_free_text":[]},"mechanistic_narrative":"TMUB1 (also known as HOPS) is a ubiquitin-like domain-containing shuttling protein that regulates protein stability, localization, and turnover across multiple cellular contexts. It retains cytoplasmic p53 by binding it and competing with importin-α for nuclear import, thereby promoting p53 mitochondrial recruitment and intrinsic apoptosis; Hops−/− mice show reduced apoptosis upon chemotherapeutic challenge [PMID:31867855]. TMUB1 stabilizes PD-L1 in the endoplasmic reticulum by competing with the E3 ligase HUWE1 to block polyubiquitination at K281 and by recruiting the oligosaccharyltransferase STT3A to enhance N-glycosylation, thereby promoting PD-L1 maturation and tumor immune evasion [PMID:36376293]. Additional functions include facilitating synaptic surface recycling of GluR2-containing AMPA receptors through interaction with GluR2 and GRIP [PMID:18665261], and forming a trimeric complex with nucleophosmin (NPM) and p19(Arf) that stabilizes p19(Arf), controls its nucleolar localization, and prevents centrosome hyperamplification [PMID:22890319]."},"prefetch_data":{"uniprot":{"accession":"Q9BVT8","full_name":"Transmembrane and ubiquitin-like domain-containing protein 1","aliases":["Dendritic cell-derived ubiquitin-like protein","DULP","Hepatocyte odd protein shuttling protein","Ubiquitin-like protein SB144"],"length_aa":246,"mass_kda":26.3,"function":"Involved in sterol-regulated ubiquitination and degradation of HMG-CoA reductase HMGCR (PubMed:21343306). Involved in positive regulation of AMPA-selective glutamate receptor GRIA2 recycling to the cell surface (By similarity). Acts as a negative regulator of hepatocyte growth during regeneration (By similarity) May contribute to the regulation of translation during cell-cycle progression. May contribute to the regulation of cell proliferation (By similarity). May be involved in centrosome assembly. Modulates stabilization and nucleolar localization of tumor suppressor CDKN2A and enhances association between CDKN2A and NPM1 (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Nucleus, nucleolus; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BVT8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMUB1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"NECAP1","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMUB1","total_profiled":1310},"omim":[{"mim_id":"620096","title":"RING FINGER PROTEIN 185; RNF185","url":"https://www.omim.org/entry/620096"},{"mim_id":"614792","title":"TRANSMEMBRANE AND UBIQUITIN-LIKE DOMAIN-CONTAINING PROTEIN 1; TMUB1","url":"https://www.omim.org/entry/614792"},{"mim_id":"604611","title":"RECQ PROTEIN-LIKE 2; RECQL2","url":"https://www.omim.org/entry/604611"},{"mim_id":"277700","title":"WERNER SYNDROME; WRN","url":"https://www.omim.org/entry/277700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMUB1"},"hgnc":{"alias_symbol":["SB144","HOPS"],"prev_symbol":["C7orf21"]},"alphafold":{"accession":"Q9BVT8","domains":[{"cath_id":"3.10.20.90","chopping":"102-170","consensus_level":"high","plddt":86.7899,"start":102,"end":170},{"cath_id":"1.10.12","chopping":"202-240_242-246","consensus_level":"medium","plddt":75.3514,"start":202,"end":246}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVT8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVT8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVT8-F1-predicted_aligned_error_v6.png","plddt_mean":65.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMUB1","jax_strain_url":"https://www.jax.org/strain/search?query=TMUB1"},"sequence":{"accession":"Q9BVT8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BVT8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BVT8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVT8"}},"corpus_meta":[{"pmid":"25498145","id":"PMC_25498145","title":"PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25498145","citation_count":463,"is_preprint":false},{"pmid":"23645161","id":"PMC_23645161","title":"CORVET and HOPS tethering complexes - coordinators of endosome and lysosome fusion.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23645161","citation_count":416,"is_preprint":false},{"pmid":"15231405","id":"PMC_15231405","title":"Xanthohumol and related prenylflavonoids from hops and beer: to your good health!","date":"2004","source":"Phytochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15231405","citation_count":407,"is_preprint":false},{"pmid":"33422265","id":"PMC_33422265","title":"ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation.","date":"2020","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/33422265","citation_count":301,"is_preprint":false},{"pmid":"10418944","id":"PMC_10418944","title":"Antiproliferative and cytotoxic effects of prenylated flavonoids from hops (Humulus lupulus) in human cancer cell lines.","date":"1999","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/10418944","citation_count":281,"is_preprint":false},{"pmid":"22308417","id":"PMC_22308417","title":"Molecular architecture of the multisubunit homotypic fusion and vacuole protein sorting (HOPS) tethering complex.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22308417","citation_count":231,"is_preprint":false},{"pmid":"24554766","id":"PMC_24554766","title":"Interaction of the HOPS complex with Syntaxin 17 mediates autophagosome clearance in Drosophila.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/24554766","citation_count":211,"is_preprint":false},{"pmid":"16601699","id":"PMC_16601699","title":"Purification of active HOPS complex reveals its affinities for phosphoinositides and the SNARE Vam7p.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16601699","citation_count":210,"is_preprint":false},{"pmid":"23351085","id":"PMC_23351085","title":"Tethering complexes in the endocytic pathway: CORVET and HOPS.","date":"2013","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/23351085","citation_count":156,"is_preprint":false},{"pmid":"16563612","id":"PMC_16563612","title":"Xanthohumol, a prenylflavonoid derived from hops induces apoptosis and inhibits NF-kappaB activation in prostate epithelial cells.","date":"2006","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/16563612","citation_count":138,"is_preprint":false},{"pmid":"19000840","id":"PMC_19000840","title":"Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of notch in the endosomal trafficking pathway.","date":"2008","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/19000840","citation_count":134,"is_preprint":false},{"pmid":"25783203","id":"PMC_25783203","title":"Recruitment of VPS33A to HOPS by VPS16 Is Required for Lysosome Fusion with Endosomes and Autophagosomes.","date":"2015","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/25783203","citation_count":125,"is_preprint":false},{"pmid":"15684030","id":"PMC_15684030","title":"The vacuolar kinase Yck3 maintains organelle fragmentation by regulating the HOPS tethering complex.","date":"2005","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15684030","citation_count":125,"is_preprint":false},{"pmid":"25908847","id":"PMC_25908847","title":"The small GTPase Arl8b regulates assembly of the mammalian HOPS complex on lysosomes.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25908847","citation_count":124,"is_preprint":false},{"pmid":"20604902","id":"PMC_20604902","title":"Defined subunit arrangement and rab interactions are required for functionality of the HOPS tethering complex.","date":"2010","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/20604902","citation_count":122,"is_preprint":false},{"pmid":"15889152","id":"PMC_15889152","title":"Sec17p and HOPS, in distinct SNARE complexes, mediate SNARE complex disruption or assembly for fusion.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15889152","citation_count":100,"is_preprint":false},{"pmid":"23167963","id":"PMC_23167963","title":"The HOPS proteins hVps41 and hVps39 are required for homotypic and heterotypic late endosome fusion.","date":"2012","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/23167963","citation_count":98,"is_preprint":false},{"pmid":"31092635","id":"PMC_31092635","title":"CORVET, CHEVI and HOPS - multisubunit tethers of the endo-lysosomal system in health and disease.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31092635","citation_count":96,"is_preprint":false},{"pmid":"32808683","id":"PMC_32808683","title":"Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.","date":"2020","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32808683","citation_count":94,"is_preprint":false},{"pmid":"12520174","id":"PMC_12520174","title":"Inhibitors of nitric oxide production from hops (Humulus lupulus L.).","date":"2003","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/12520174","citation_count":91,"is_preprint":false},{"pmid":"8392474","id":"PMC_8392474","title":"Site-specific genetic recombination: hops, flips, and flops.","date":"1993","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/8392474","citation_count":91,"is_preprint":false},{"pmid":"16076101","id":"PMC_16076101","title":"Comparison of the in vitro estrogenic activities of compounds from hops (Humulus lupulus) and red clover (Trifolium pratense).","date":"2005","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16076101","citation_count":89,"is_preprint":false},{"pmid":"26463206","id":"PMC_26463206","title":"Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26463206","citation_count":85,"is_preprint":false},{"pmid":"28914604","id":"PMC_28914604","title":"Scc2/Nipbl hops between chromosomal cohesin rings after loading.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28914604","citation_count":83,"is_preprint":false},{"pmid":"31842945","id":"PMC_31842945","title":"HOPS: automated detection and authentication of pathogen DNA in archaeological remains.","date":"2019","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/31842945","citation_count":82,"is_preprint":false},{"pmid":"19193765","id":"PMC_19193765","title":"Vps41 phosphorylation and the Rab Ypt7 control the targeting of the HOPS complex to endosome-vacuole fusion sites.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19193765","citation_count":82,"is_preprint":false},{"pmid":"28306502","id":"PMC_28306502","title":"Pacer Mediates the Function of Class III PI3K and HOPS Complexes in Autophagosome Maturation by Engaging Stx17.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28306502","citation_count":81,"is_preprint":false},{"pmid":"23901104","id":"PMC_23901104","title":"Structural basis of Vps33A recruitment to the human HOPS complex by Vps16.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23901104","citation_count":81,"is_preprint":false},{"pmid":"20087858","id":"PMC_20087858","title":"Xanthohumol, a chalcon derived from hops, inhibits hepatic inflammation and fibrosis.","date":"2010","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/20087858","citation_count":76,"is_preprint":false},{"pmid":"21613544","id":"PMC_21613544","title":"HOPS drives vacuole fusion by binding the vacuolar SNARE complex and the Vam7 PX domain via two distinct sites.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21613544","citation_count":76,"is_preprint":false},{"pmid":"30272303","id":"PMC_30272303","title":"Xanthohumol, a prenylated flavonoid from Hops, exerts anticancer effects against gastric cancer in vitro.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/30272303","citation_count":75,"is_preprint":false},{"pmid":"36376293","id":"PMC_36376293","title":"Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36376293","citation_count":74,"is_preprint":false},{"pmid":"19741093","id":"PMC_19741093","title":"HOPS interacts with Apl5 at the vacuole membrane and is required for consumption of AP-3 transport vesicles.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19741093","citation_count":73,"is_preprint":false},{"pmid":"36098503","id":"PMC_36098503","title":"Structure of the HOPS tethering complex, a lysosomal membrane fusion machinery.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36098503","citation_count":72,"is_preprint":false},{"pmid":"11038156","id":"PMC_11038156","title":"Prenylflavonoids from hops inhibit the metabolic activation of the carcinogenic heterocyclic amine 2-amino-3-methylimidazo[4, 5-f]quinoline, mediated by cDNA-expressed human CYP1A2.","date":"2000","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/11038156","citation_count":71,"is_preprint":false},{"pmid":"27428774","id":"PMC_27428774","title":"CATCHR, HOPS and CORVET tethering complexes share a similar architecture.","date":"2016","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27428774","citation_count":70,"is_preprint":false},{"pmid":"20194640","id":"PMC_20194640","title":"The novel endosomal membrane protein Ema interacts with the class C Vps-HOPS complex to promote endosomal maturation.","date":"2010","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20194640","citation_count":66,"is_preprint":false},{"pmid":"25217511","id":"PMC_25217511","title":"Adjustment of host cells for accommodation of symbiotic bacteria: vacuole defunctionalization, HOPS suppression, and TIP1g retargeting in Medicago.","date":"2014","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/25217511","citation_count":62,"is_preprint":false},{"pmid":"24897556","id":"PMC_24897556","title":"Xanthohumol, a prenylated chalcone from beer hops, acts as an α-glucosidase inhibitor in vitro.","date":"2014","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24897556","citation_count":60,"is_preprint":false},{"pmid":"20043079","id":"PMC_20043079","title":"Xanthohumol, a prenylated chalcone derived from hops, inhibits proliferation, migration and interleukin-8 expression of hepatocellular carcinoma cells.","date":"2010","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20043079","citation_count":57,"is_preprint":false},{"pmid":"30608650","id":"PMC_30608650","title":"The Multiple Biological Targets of Hops and Bioactive Compounds.","date":"2019","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/30608650","citation_count":55,"is_preprint":false},{"pmid":"19109425","id":"PMC_19109425","title":"SPE-39 family proteins interact with the HOPS complex and function in lysosomal delivery.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19109425","citation_count":55,"is_preprint":false},{"pmid":"24088569","id":"PMC_24088569","title":"The tethering complex HOPS catalyzes assembly of the soluble SNARE Vam7 into fusogenic trans-SNARE complexes.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/24088569","citation_count":54,"is_preprint":false},{"pmid":"28559361","id":"PMC_28559361","title":"Adaptor Protein-3-Dependent Vacuolar Trafficking Involves a Subpopulation of COPII and HOPS Tethering Proteins.","date":"2017","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28559361","citation_count":53,"is_preprint":false},{"pmid":"18768384","id":"PMC_18768384","title":"Structural basis of human pregnane X receptor activation by the hops constituent colupulone.","date":"2008","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18768384","citation_count":53,"is_preprint":false},{"pmid":"18087812","id":"PMC_18087812","title":"Inhibition of topoisomerase I activity and efflux drug transporters' expression by xanthohumol. from hops.","date":"2007","source":"Archives of pharmacal research","url":"https://pubmed.ncbi.nlm.nih.gov/18087812","citation_count":51,"is_preprint":false},{"pmid":"23935502","id":"PMC_23935502","title":"The late endosomal HOPS complex anchors active G-protein signaling essential for pathogenesis in magnaporthe oryzae.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/23935502","citation_count":49,"is_preprint":false},{"pmid":"29084291","id":"PMC_29084291","title":"Salmonella exploits the host endolysosomal tethering factor HOPS complex to promote its intravacuolar replication.","date":"2017","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/29084291","citation_count":48,"is_preprint":false},{"pmid":"15636177","id":"PMC_15636177","title":"In vitro binding experiments with a Valerian, hops and their fixed combination extract (Ze91019) to selected central nervous system receptors.","date":"2004","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15636177","citation_count":47,"is_preprint":false},{"pmid":"38177132","id":"PMC_38177132","title":"De novo biosynthesis of the hops bioactive flavonoid xanthohumol in yeast.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38177132","citation_count":46,"is_preprint":false},{"pmid":"25640905","id":"PMC_25640905","title":"Toxoplasma gondii Vps11, a subunit of HOPS and CORVET tethering complexes, is essential for the biogenesis of secretory organelles.","date":"2015","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25640905","citation_count":44,"is_preprint":false},{"pmid":"30104351","id":"PMC_30104351","title":"Phosphoinositides control the localization of HOPS subunit VPS41, which together with VPS33 mediates vacuole fusion in plants.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30104351","citation_count":44,"is_preprint":false},{"pmid":"21148287","id":"PMC_21148287","title":"The ERM proteins interact with the HOPS complex to regulate the maturation of endosomes.","date":"2010","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21148287","citation_count":44,"is_preprint":false},{"pmid":"29946343","id":"PMC_29946343","title":"Novel anti-obesity effects of beer hops compound xanthohumol: role of AMPK signaling pathway.","date":"2018","source":"Nutrition & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29946343","citation_count":43,"is_preprint":false},{"pmid":"30610181","id":"PMC_30610181","title":"HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30610181","citation_count":42,"is_preprint":false},{"pmid":"28036030","id":"PMC_28036030","title":"Xanthohumol, a Prenylated Chalcone from Hops, Inhibits the Viability and Stemness of Doxorubicin-Resistant MCF-7/ADR Cells.","date":"2016","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/28036030","citation_count":42,"is_preprint":false},{"pmid":"33851776","id":"PMC_33851776","title":"Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation.","date":"2021","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33851776","citation_count":41,"is_preprint":false},{"pmid":"33764426","id":"PMC_33764426","title":"Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.","date":"2021","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33764426","citation_count":41,"is_preprint":false},{"pmid":"36640308","id":"PMC_36640308","title":"Consecutive functions of small GTPases guide HOPS-mediated tethering of late endosomes and lysosomes.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36640308","citation_count":40,"is_preprint":false},{"pmid":"26620037","id":"PMC_26620037","title":"Inhibition of Osteoclastogenesis and Bone Resorption in vitro and in vivo by a prenylflavonoid xanthohumol from hops.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26620037","citation_count":40,"is_preprint":false},{"pmid":"23669332","id":"PMC_23669332","title":"Xanthohumol, a main prenylated chalcone from hops, reduces liver damage and modulates oxidative reaction and apoptosis in hepatitis C virus infected Tupaia belangeri.","date":"2013","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23669332","citation_count":39,"is_preprint":false},{"pmid":"16715376","id":"PMC_16715376","title":"In vitro studies of intestinal permeability and hepatic and intestinal metabolism of 8-prenylnaringenin, a potent phytoestrogen from hops (Humulus lupulus L.).","date":"2006","source":"Pharmaceutical research","url":"https://pubmed.ncbi.nlm.nih.gov/16715376","citation_count":37,"is_preprint":false},{"pmid":"23245320","id":"PMC_23245320","title":"Impaired stimulation of p38α-MAPK/Vps41-HOPS by LPS from pathogenic Coxiella burnetii prevents trafficking to microbicidal phagolysosomes.","date":"2012","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/23245320","citation_count":37,"is_preprint":false},{"pmid":"16685279","id":"PMC_16685279","title":"Molecular phylogeny of wild hops, Humulus lupulus L.","date":"2006","source":"Heredity","url":"https://pubmed.ncbi.nlm.nih.gov/16685279","citation_count":36,"is_preprint":false},{"pmid":"21997247","id":"PMC_21997247","title":"Hops (Humulus lupulus) inhibits oxidative estrogen metabolism and estrogen-induced malignant transformation in human mammary epithelial cells (MCF-10A).","date":"2011","source":"Cancer prevention research (Philadelphia, Pa.)","url":"https://pubmed.ncbi.nlm.nih.gov/21997247","citation_count":35,"is_preprint":false},{"pmid":"16014383","id":"PMC_16014383","title":"HOPS: a novel cAMP-dependent shuttling protein involved in protein synthesis regulation.","date":"2005","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16014383","citation_count":34,"is_preprint":false},{"pmid":"14525933","id":"PMC_14525933","title":"Comprehensive analysis of orthologous protein domains using the HOPS database.","date":"2003","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/14525933","citation_count":33,"is_preprint":false},{"pmid":"32840906","id":"PMC_32840906","title":"AP-3 vesicle uncoating occurs after HOPS-dependent vacuole tethering.","date":"2020","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/32840906","citation_count":32,"is_preprint":false},{"pmid":"32290112","id":"PMC_32290112","title":"Xanthohumol, a Prenylated Flavonoid from Hops, Induces DNA Damages in Colorectal Cancer Cells and Sensitizes SW480 Cells to the SN38 Chemotherapeutic Agent.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32290112","citation_count":32,"is_preprint":false},{"pmid":"23512484","id":"PMC_23512484","title":"Differential regulation of detoxification enzymes in hepatic and mammary tissue by hops (Humulus lupulus) in vitro and in vivo.","date":"2013","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/23512484","citation_count":32,"is_preprint":false},{"pmid":"25564619","id":"PMC_25564619","title":"The Habc domain of the SNARE Vam3 interacts with the HOPS tethering complex to facilitate vacuole fusion.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25564619","citation_count":32,"is_preprint":false},{"pmid":"26211581","id":"PMC_26211581","title":"The inhibitory effects of xanthohumol, a prenylated chalcone derived from hops, on cell growth and tumorigenesis in human pancreatic cancer.","date":"2015","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/26211581","citation_count":30,"is_preprint":false},{"pmid":"26840505","id":"PMC_26840505","title":"Impact of xanthohumol (a prenylated flavonoid from hops) on DNA stability and other health-related biochemical parameters: Results of human intervention trials.","date":"2016","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/26840505","citation_count":30,"is_preprint":false},{"pmid":"31867855","id":"PMC_31867855","title":"HOPS/TMUB1 retains p53 in the cytoplasm and sustains p53-dependent mitochondrial apoptosis.","date":"2019","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/31867855","citation_count":29,"is_preprint":false},{"pmid":"22787280","id":"PMC_22787280","title":"Phosphorylation of the effector complex HOPS by the vacuolar kinase Yck3p confers Rab nucleotide specificity for vacuole docking and fusion.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22787280","citation_count":29,"is_preprint":false},{"pmid":"18814205","id":"PMC_18814205","title":"Inhibitory effects of xanthohumol from hops (Humulus lupulus L.) on human hepatocellular carcinoma cell lines.","date":"2008","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/18814205","citation_count":29,"is_preprint":false},{"pmid":"31269943","id":"PMC_31269943","title":"Disruption of vacuolar protein sorting components of the HOPS complex leads to enhanced secretion of recombinant proteins in Pichia pastoris.","date":"2019","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/31269943","citation_count":28,"is_preprint":false},{"pmid":"25948753","id":"PMC_25948753","title":"Regulation of lipid droplet dynamics in Saccharomyces cerevisiae depends on the Rab7-like Ypt7p, HOPS complex and V1-ATPase.","date":"2015","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/25948753","citation_count":28,"is_preprint":false},{"pmid":"37821429","id":"PMC_37821429","title":"C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37821429","citation_count":27,"is_preprint":false},{"pmid":"33938619","id":"PMC_33938619","title":"Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease.","date":"2021","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33938619","citation_count":27,"is_preprint":false},{"pmid":"24498211","id":"PMC_24498211","title":"KDT501, a derivative from hops, normalizes glucose metabolism and body weight in rodent models of diabetes.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24498211","citation_count":26,"is_preprint":false},{"pmid":"30458450","id":"PMC_30458450","title":"6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30458450","citation_count":25,"is_preprint":false},{"pmid":"17460388","id":"PMC_17460388","title":"Isohumulones derived from hops ameliorate renal injury via an anti-oxidative effect in Dahl salt-sensitive rats.","date":"2007","source":"Hypertension research : official journal of the Japanese Society of Hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/17460388","citation_count":25,"is_preprint":false},{"pmid":"31194677","id":"PMC_31194677","title":"Vps8 overexpression inhibits HOPS-dependent trafficking routes by outcompeting Vps41/Lt.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31194677","citation_count":24,"is_preprint":false},{"pmid":"35417008","id":"PMC_35417008","title":"Arabidopsis HOPS subunit VPS41 carries out plant-specific roles in vacuolar transport and vegetative growth.","date":"2022","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35417008","citation_count":24,"is_preprint":false},{"pmid":"18665261","id":"PMC_18665261","title":"Transmembrane and ubiquitin-like domain-containing protein 1 (Tmub1/HOPS) facilitates surface expression of GluR2-containing AMPA receptors.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18665261","citation_count":24,"is_preprint":false},{"pmid":"18066133","id":"PMC_18066133","title":"Clinical safety and efficacy of NG440: a novel combination of rho iso-alpha acids from hops, rosemary, and oleanolic acid for inflammatory conditions.","date":"2007","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18066133","citation_count":24,"is_preprint":false},{"pmid":"32540926","id":"PMC_32540926","title":"Yeast phosphatidic acid phosphatase Pah1 hops and scoots along the membrane phospholipid bilayer.","date":"2020","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/32540926","citation_count":23,"is_preprint":false},{"pmid":"22890319","id":"PMC_22890319","title":"Hepatocyte odd protein shuttling (HOPS) is a bridging protein in the nucleophosmin-p19 Arf network.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22890319","citation_count":23,"is_preprint":false},{"pmid":"21411634","id":"PMC_21411634","title":"Clathrin-dependent mechanisms modulate the subcellular distribution of class C Vps/HOPS tether subunits in polarized and nonpolarized cells.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21411634","citation_count":23,"is_preprint":false},{"pmid":"33572775","id":"PMC_33572775","title":"Xanthohumol, a Prenylated Chalcone Derived from Hops, Inhibits Growth and Metastasis of Melanoma Cells.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33572775","citation_count":23,"is_preprint":false},{"pmid":"29597299","id":"PMC_29597299","title":"Synthesis and Antiproliferative Activity of Minor Hops Prenylflavonoids and New Insights on Prenyl Group Cyclization.","date":"2018","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/29597299","citation_count":22,"is_preprint":false},{"pmid":"18822279","id":"PMC_18822279","title":"Genetic and epigenetic stability of cryopreserved and cold-stored hops (Humulus lupulus L.).","date":"2008","source":"Cryobiology","url":"https://pubmed.ncbi.nlm.nih.gov/18822279","citation_count":22,"is_preprint":false},{"pmid":"24501423","id":"PMC_24501423","title":"Caenorhabditis elegans HOPS and CCZ-1 mediate trafficking to lysosome-related organelles independently of RAB-7 and SAND-1.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/24501423","citation_count":22,"is_preprint":false},{"pmid":"27307091","id":"PMC_27307091","title":"The HOPS/Class C Vps Complex Tethers High-Curvature Membranes via a Direct Protein-Membrane Interaction.","date":"2016","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/27307091","citation_count":22,"is_preprint":false},{"pmid":"28931724","id":"PMC_28931724","title":"VPS18 recruits VPS41 to the human HOPS complex via a RING-RING interaction.","date":"2017","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/28931724","citation_count":21,"is_preprint":false},{"pmid":"22357954","id":"PMC_22357954","title":"SNAREs, HOPS and regulatory lipids control the dynamics of vacuolar actin during homotypic fusion in S. cerevisiae.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22357954","citation_count":21,"is_preprint":false},{"pmid":"27617238","id":"PMC_27617238","title":"Hops for Menopausal Vasomotor Symptoms: Mechanisms of Action.","date":"2016","source":"Journal of menopausal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27617238","citation_count":21,"is_preprint":false},{"pmid":"19413813","id":"PMC_19413813","title":"The antimicrobial effects of hops (Humulus lupulus L.) on ruminal hyper ammonia-producing bacteria.","date":"2009","source":"Letters in applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19413813","citation_count":21,"is_preprint":false},{"pmid":"35106609","id":"PMC_35106609","title":"Hops extract and xanthohumol ameliorate bone loss induced by iron overload via activating Akt/GSK3β/Nrf2 pathway.","date":"2022","source":"Journal of bone and mineral metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/35106609","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47090,"output_tokens":1571,"usd":0.082418},"stage2":{"model":"claude-opus-4-6","input_tokens":4821,"output_tokens":2085,"usd":0.114345},"total_usd":0.196763,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"TMUB1 (HOPS/Hepatocyte Odd Protein Shuttling) is a shuttling protein that binds elongation factor eEF-1A and interferes with protein synthesis. Its nuclear export is governed by cAMP signaling and mediated via the CRM-1 export receptor. Overexpression strongly reduces cell proliferation.\",\n      \"method\": \"Regenerating liver cDNA library screen; co-immunoprecipitation with eEF-1A; cAMP/CRM-1 export assays; overexpression in H-35 and 3T3-NIH cells with proliferation readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab, multiple orthogonal methods (binding assay, nuclear export assay, functional overexpression), but not independently replicated\",\n      \"pmids\": [\"16014383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TMUB1 (Tmub1/HOPS) facilitates surface recycling of GluR2-containing AMPA receptors. It is enriched in synaptosomal membranes, co-immunoprecipitates with GluR2 and GRIP from mouse brain, and its knockdown reduces AMPA receptor currents and synaptic surface expression of GluR2 (but not GluR1), while overexpression increases GluR2 surface expression.\",\n      \"method\": \"RNAi knockdown in neurons with electrophysiological readout; overexpression with surface biotinylation assay; co-immunoprecipitation from mouse brain; recycling assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with multiple orthogonal methods (electrophysiology, co-IP, surface expression, recycling assay)\",\n      \"pmids\": [\"18665261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TMUB1 (HOPS) directly interacts with nucleophosmin (NPM) and p19(Arf), forming a functionally active trimeric complex. NPM regulates HOPS half-life, while HOPS stabilizes p19(Arf) and controls its nucleolar localization. HOPS knockdown causes centrosome hyperamplification and multinucleated cells; overexpression causes G0/G1 arrest.\",\n      \"method\": \"Co-immunoprecipitation; protein stability assays; siRNA knockdown with cell cycle and centrosome phenotype readouts; overexpression with cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab, multiple orthogonal methods (co-IP, KD phenotype, OE phenotype, localization)\",\n      \"pmids\": [\"22890319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TMUB1 (HOPS) retains p53 in the cytoplasm by binding p53, inhibiting its proteasomal degradation, and interfering with importin-α to block nuclear import. This promotes p53 recruitment to mitochondria and induction of the intrinsic apoptosis pathway. Hops−/− mice show significantly reduced apoptosis upon chemotherapeutic challenge.\",\n      \"method\": \"Hops−/− mouse model; co-immunoprecipitation of HOPS with p53; importin-α interaction assay; mitochondrial fractionation; apoptosis assays in vivo and in cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo knockout mouse with defined apoptosis phenotype, co-IP with p53, importin-α competition, mitochondrial recruitment, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"31867855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMUB1 modulates PD-L1 post-translational modifications in tumor cells: it competes with the E3 ubiquitin ligase HUWE1 for interaction with PD-L1 and inhibits PD-L1 polyubiquitination at K281 in the endoplasmic reticulum. Additionally, TMUB1 recruits STT3A to enhance PD-L1 N-glycosylation and stability, promoting PD-L1 maturation and tumor immune evasion.\",\n      \"method\": \"Co-immunoprecipitation of TMUB1 with PD-L1 and HUWE1; ubiquitination assay identifying K281 site; glycosylation assays with STT3A recruitment; TMUB1 knockdown/overexpression with PD-L1 stability and immune evasion readouts; synthetic competing peptide in mouse tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (co-IP, ubiquitination site mapping, glycosylation assay, in vivo peptide competition), single rigorous study with strong mechanistic depth\",\n      \"pmids\": [\"36376293\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMUB1 (also called HOPS) is a multifunctional ubiquitin-like domain-containing shuttling protein that: (1) retains cytoplasmic p53 from proteasomal degradation and nuclear import to promote mitochondrial apoptosis; (2) stabilizes PD-L1 by inhibiting HUWE1-mediated polyubiquitination at K281 and recruiting STT3A to enhance N-glycosylation in the ER; (3) facilitates synaptic surface recycling of GluR2-containing AMPA receptors by interacting with GluR2 and GRIP; and (4) bridges NPM and p19(Arf) to regulate cell cycle progression and p19(Arf) nucleolar localization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TMUB1 (also known as HOPS) is a ubiquitin-like domain-containing shuttling protein that regulates protein stability, localization, and turnover across multiple cellular contexts. It retains cytoplasmic p53 by binding it and competing with importin-α for nuclear import, thereby promoting p53 mitochondrial recruitment and intrinsic apoptosis; Hops−/− mice show reduced apoptosis upon chemotherapeutic challenge [PMID:31867855]. TMUB1 stabilizes PD-L1 in the endoplasmic reticulum by competing with the E3 ligase HUWE1 to block polyubiquitination at K281 and by recruiting the oligosaccharyltransferase STT3A to enhance N-glycosylation, thereby promoting PD-L1 maturation and tumor immune evasion [PMID:36376293]. Additional functions include facilitating synaptic surface recycling of GluR2-containing AMPA receptors through interaction with GluR2 and GRIP [PMID:18665261], and forming a trimeric complex with nucleophosmin (NPM) and p19(Arf) that stabilizes p19(Arf), controls its nucleolar localization, and prevents centrosome hyperamplification [PMID:22890319].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of TMUB1 as a nucleocytoplasmic shuttling protein that binds eEF-1A and suppresses proliferation established it as a functionally active signaling intermediary rather than a passive structural component.\",\n      \"evidence\": \"Regenerating liver cDNA screen; co-IP with eEF-1A; CRM-1 export and cAMP regulation assays; overexpression growth suppression in H-35 and 3T3-NIH cells\",\n      \"pmids\": [\"16014383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which eEF-1A binding suppresses translation not delineated\",\n        \"Findings from a single lab without independent replication\",\n        \"In vivo relevance of the proliferation-suppressive effect not tested\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that TMUB1 selectively promotes surface recycling of GluR2-containing AMPA receptors expanded its role to post-synaptic membrane trafficking, answering how GluR2 surface levels are maintained at synapses.\",\n      \"evidence\": \"RNAi knockdown in neurons with electrophysiology; surface biotinylation; co-IP of TMUB1 with GluR2 and GRIP from mouse brain; recycling assay\",\n      \"pmids\": [\"18665261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study without independent replication\",\n        \"Structural basis of the TMUB1–GluR2–GRIP interaction unknown\",\n        \"Whether TMUB1 functions in long-term synaptic plasticity not tested\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery of a TMUB1–NPM–p19(Arf) trimeric complex revealed how TMUB1 integrates nucleolar surveillance with cell cycle control, explaining centrosome hyperamplification upon TMUB1 loss.\",\n      \"evidence\": \"Co-IP; protein stability assays; siRNA knockdown with centrosome and cell cycle phenotypes; overexpression inducing G0/G1 arrest\",\n      \"pmids\": [\"22890319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; trimeric complex not reconstituted in vitro\",\n        \"Whether TMUB1 loss causes centrosome defects through p19(Arf)-dependent or -independent pathways not resolved\",\n        \"Relevance of the complex to tumorigenesis in vivo not established\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Using knockout mice, the p53-retention mechanism was resolved: TMUB1 competes with importin-α for p53 binding, blocking nuclear import and channeling p53 to mitochondria to activate intrinsic apoptosis—the first in vivo demonstration of TMUB1 function.\",\n      \"evidence\": \"Hops−/− mouse model; co-IP of TMUB1 with p53; importin-α competition assay; mitochondrial fractionation; in vivo apoptosis upon chemotherapy\",\n      \"pmids\": [\"31867855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TMUB1–p53 interaction is direct or requires bridging factors not structurally resolved\",\n        \"Relative contributions of p53 stabilization versus nuclear import blockade not quantitatively separated\",\n        \"Tumor-suppressive consequences of TMUB1 loss not formally tested in cancer models\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The PD-L1 stabilization mechanism answered how tumor cells upregulate immune checkpoint ligands post-translationally: TMUB1 outcompetes HUWE1 at K281 to prevent polyubiquitination and recruits STT3A for N-glycosylation, establishing TMUB1 as a targetable node in immune evasion.\",\n      \"evidence\": \"Co-IP of TMUB1 with PD-L1 and HUWE1; ubiquitination site mapping at K281; glycosylation assay with STT3A; TMUB1 KD/OE with PD-L1 stability readout; competing peptide in mouse tumor models\",\n      \"pmids\": [\"36376293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TMUB1-mediated PD-L1 stabilization occurs in all tumor types or is context-dependent\",\n        \"Structural basis of TMUB1 competition with HUWE1 unknown\",\n        \"Whether TMUB1 regulates glycosylation of other ER clients besides PD-L1 not examined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No structural model of TMUB1 exists, and how a single shuttling protein coordinates such diverse substrates (p53, PD-L1, GluR2, NPM/Arf) through its ubiquitin-like domain and transmembrane segments remains mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of TMUB1 or any of its complexes\",\n        \"How substrate selectivity is achieved across ER, cytoplasm, and synaptic compartments unknown\",\n        \"Functional significance of the ubiquitin-like domain not dissected by mutagenesis across all interaction partners\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"NPM–p19(Arf)–TMUB1 trimeric complex\"\n    ],\n    \"partners\": [\n      \"TP53\",\n      \"CD274\",\n      \"HUWE1\",\n      \"STT3A\",\n      \"NPM1\",\n      \"CDKN2A\",\n      \"GRIA2\",\n      \"GRIP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}