{"gene":"TNPO1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2017,"finding":"TNPO1 (transportin-1) mediates nuclear import of the LINE-1 ribonucleoprotein complex (using ORF1p as a proxy); induction or depletion of TNPO1 directly affects L1 retrotransposition and nuclear import of the L1-RNP, and TNPO1 overexpression partially reverses the repressive effect of miR-128 on L1 retrotransposition.","method":"Overexpression and knockdown of TNPO1 combined with L1 retrotransposition reporter assay and nuclear import assay for ORF1p","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gain- and loss-of-function experiments with specific phenotypic readout (retrotransposition and nuclear import), single lab, two orthogonal functional assays","pmids":["28974576"],"is_preprint":false},{"year":2021,"finding":"TNPO1 mediates nuclear import of FUBP1 (far upstream element binding protein 1) in cervical cancer cells; FUBP1 physically interacts with TNPO1, and nuclear localization of FUBP1 — dependent on this interaction — drives transcriptional regulation of the immune checkpoint gene NRP1.","method":"Co-immunoprecipitation (FUBP1–TNPO1 interaction), knockdown experiments, subcellular fractionation, and gene expression analysis of NRP1","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP interaction plus functional knockdown with downstream gene expression phenotype, single lab","pmids":["33987449"],"is_preprint":false},{"year":2021,"finding":"TNPO1 selectively mediates nuclear import of ARID1B in gynecologic cancer cells; loss of TNPO1 or ARID1B reduces chromatin accessibility, depletes H3K4me1 and H3K27ac histone marks, diminishes AP-1 transcription factor activity, and inactivates PI3K/AKT signaling by reducing PIK3CA and FGFR2 expression.","method":"Genetic knockdown (in vitro and in vivo xenograft), chromatin accessibility assay (ATAC-seq implied), ChIP for histone marks, gene expression profiling","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal downstream readouts (chromatin, histone marks, signaling pathway), single lab","pmids":["34044070"],"is_preprint":false},{"year":2020,"finding":"PPARγ2 forms a redox-dependent complex with Tnpo1 via disulfide bonds between Cys176/Cys180 of PPARγ2 and Cys512 of Tnpo1; H2O2-driven complex formation enhances nuclear translocation of PPARγ2, increases DNA-bound PPARγ, and promotes downstream signaling leading to hepatic triglyceride accumulation.","method":"Co-immunoprecipitation, cysteine mutagenesis, hepatocyte culture overexpression/knockdown, mouse models, subcellular fractionation","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-IP with mutagenesis identifying specific cysteine residues, functional validation in both cell culture and mouse models, multiple orthogonal methods in one study","pmids":["32553752"],"is_preprint":false},{"year":2023,"finding":"TNPO1 directly binds the ciliary targeting sequence (CTS) of Arl13b — a C-terminal 17-amino-acid stretch containing the RVEP motif — together with Rab8-GDP (but not Rab8-GTP); Rab8-GDP substantially enhances TNPO1–CTS interaction, and knockdown of endogenous TNPO1 decreases ciliary localization of Arl13b.","method":"Pull-down assays with cell lysates and purified recombinant proteins, TurboID-based proximity ligation, RVEP point-mutation analysis, siRNA knockdown with ciliary imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins, mutagenesis of the RVEP motif, proximity ligation, and knockdown phenotype, multiple orthogonal methods","pmids":["36907439"],"is_preprint":false},{"year":2026,"finding":"TNPO1, together with Rab8, functions as a ciliary transport adapter for multiple cilium-localized GPCRs; for β2 adrenergic receptor, TNPO1 and Rab8 interact specifically with the C-terminal CTS (not the third intracellular loop CTS), and both adapters are required for ciliary localization of this GPCR.","method":"Pull-down interaction screening of nine ciliary GPCRs, CTS truncation/mutation mapping, siRNA knockdown of Rab8 and TNPO1 with ciliary localization readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic interaction screen with mutagenesis and knockdown phenotype, single lab, extends prior reconstitution work","pmids":["42036045"],"is_preprint":false}],"current_model":"TNPO1 (transportin-1/karyopherin-β2) is a nuclear and ciliary import receptor that recognizes diverse cargoes — including LINE-1 RNPs, FUBP1, ARID1B, and PPARγ2 (the latter via redox-sensitive disulfide bonds involving Cys512) — to mediate their nuclear translocation, and also functions together with Rab8-GDP as a ciliary transport adapter for Arl13b and multiple GPCRs by binding RVEP-containing ciliary targeting sequences."},"narrative":{"mechanistic_narrative":"TNPO1 (transportin-1) is a soluble nuclear/ciliary import receptor that recognizes diverse cargoes through dedicated targeting determinants to direct their subcellular localization [PMID:32553752, PMID:36907439]. In its classic nuclear-import role it mediates translocation of multiple cargoes, including the LINE-1 ribonucleoprotein (where TNPO1 levels set the rate of L1 retrotransposition) [PMID:28974576], FUBP1 (whose TNPO1-dependent nuclear accumulation drives transcription of the immune checkpoint gene NRP1) [PMID:33987449], and the chromatin remodeler ARID1B (loss of which reduces chromatin accessibility, depletes H3K4me1/H3K27ac, and impairs AP-1 and PI3K/AKT signaling) [PMID:34044070]. Cargo engagement can be redox-gated: TNPO1 forms an H2O2-induced disulfide complex with PPARγ2 via Cys512 of TNPO1 and Cys176/Cys180 of PPARγ2, enhancing PPARγ2 nuclear entry and promoting hepatic triglyceride accumulation [PMID:32553752]. Beyond the nucleus, TNPO1 acts as a ciliary transport adapter: together with Rab8-GDP it binds RVEP-motif ciliary targeting sequences to deliver Arl13b and multiple GPCRs, including the β2 adrenergic receptor, to the cilium, with Rab8-GDP strongly enhancing recognition of the targeting sequence [PMID:36907439, PMID:42036045].","teleology":[{"year":2017,"claim":"Established TNPO1 as the import factor controlling nuclear entry of the LINE-1 RNP, linking it to retrotransposon mobility rather than only canonical protein cargoes.","evidence":"TNPO1 overexpression/knockdown with L1 retrotransposition reporter and ORF1p nuclear import assays","pmids":["28974576"],"confidence":"Medium","gaps":["Does not define the targeting motif on the L1-RNP recognized by TNPO1","Whether TNPO1 binds ORF1p directly or via another adaptor is not resolved"]},{"year":2020,"claim":"Showed that TNPO1 cargo recognition can be redox-regulated, identifying a specific disulfide interface (TNPO1 Cys512 with PPARγ2 Cys176/Cys180) that couples oxidative state to nuclear import.","evidence":"Co-IP, cysteine mutagenesis, hepatocyte overexpression/knockdown, and mouse models","pmids":["32553752"],"confidence":"High","gaps":["Whether redox gating applies to other TNPO1 cargoes is untested","Structural basis of the disulfide-stabilized complex is not determined"]},{"year":2021,"claim":"Extended TNPO1 cargo repertoire to transcription/chromatin regulators (FUBP1 and ARID1B), connecting its import function to downstream transcriptional and chromatin outputs in cancer.","evidence":"Co-IP, knockdown, subcellular fractionation, chromatin accessibility and ChIP assays in cancer cells","pmids":["33987449","34044070"],"confidence":"Medium","gaps":["Targeting sequences on FUBP1 and ARID1B recognized by TNPO1 are not mapped","Cargo selectivity versus other karyopherins is not established"]},{"year":2023,"claim":"Revealed a non-nuclear function: TNPO1 acts with Rab8-GDP as a ciliary transport adapter that recognizes an RVEP-containing ciliary targeting sequence on Arl13b.","evidence":"Pull-downs with purified proteins, TurboID proximity ligation, RVEP point mutagenesis, and siRNA with ciliary imaging","pmids":["36907439"],"confidence":"High","gaps":["Mechanism by which a nuclear import receptor is repurposed for ciliary delivery is unclear","How Rab8 nucleotide state is coordinated with cargo handoff at the cilium is unknown"]},{"year":2026,"claim":"Generalized the ciliary adapter role, showing TNPO1/Rab8 recognize C-terminal CTSs of multiple ciliary GPCRs and are required for their ciliary localization.","evidence":"Interaction screening of nine ciliary GPCRs, CTS truncation/mutation mapping, and Rab8/TNPO1 siRNA with ciliary localization readout","pmids":["42036045"],"confidence":"Medium","gaps":["Consensus features defining a TNPO1-recognized ciliary CTS are not fully defined","In vitro reconstitution with purified GPCR CTSs is not reported"]},{"year":null,"claim":"It remains unresolved how TNPO1 partitions between nuclear-import and ciliary-adapter functions and what structural determinants distinguish nuclear targeting signals from RVEP ciliary targeting sequences.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of TNPO1 cargo recognition across nuclear and ciliary cargoes","Regulation of TNPO1 localization and function across compartments is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[4,5]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3,4,5]}],"complexes":[],"partners":["RAB8A","ARL13B","PPARG","FUBP1","ARID1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92973","full_name":"Transportin-1","aliases":["Importin beta-2","Karyopherin beta-2","M9 region interaction protein","MIP"],"length_aa":898,"mass_kda":102.4,"function":"Functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates (PubMed:24753571). May mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus (By similarity). Involved in nuclear import of M9-containing proteins. In vitro, binds directly to the M9 region of the heterogeneous nuclear ribonucleoproteins (hnRNP), A1 and A2 and mediates their nuclear import. Involved in hnRNP A1/A2 nuclear export. Mediates the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5 (PubMed:11682607). In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones (By similarity). In vitro, mediates nuclear import of SRP19 (PubMed:11682607). Mediates nuclear import of ADAR/ADAR1 isoform 1 and isoform 5 in a RanGTP-dependent manner (PubMed:19124606, PubMed:24753571). Main mediator of PR-DUB complex component BAP1 nuclear import; acts redundantly with the karyopherins KPNA1 and KPNA2 (PubMed:35446349) (Microbial infection) In case of HIV-1 infection, binds and mediates the nuclear import of HIV-1 Rev","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q92973/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNPO1","classification":"Not Classified","n_dependent_lines":466,"n_total_lines":1208,"dependency_fraction":0.38576158940397354},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000083312","cell_line_id":"CID001576","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nuclear_membrane","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"big_aggregates","grade":2}],"interactors":[{"gene":"NUP153","stoichiometry":10.0},{"gene":"TMA16","stoichiometry":10.0},{"gene":"ALYREF","stoichiometry":10.0},{"gene":"FUS","stoichiometry":4.0},{"gene":"HNRNPD","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"EWSR1","stoichiometry":0.2},{"gene":"HNRNPA0","stoichiometry":0.2},{"gene":"HNRNPA2B1","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001576","total_profiled":1310},"omim":[{"mim_id":"620460","title":"OCULOPHARYNGEAL MUSCULAR DYSTROPHY 2; OPMD2","url":"https://www.omim.org/entry/620460"},{"mim_id":"620067","title":"CARDIAC VALVULAR DYSPLASIA 2; CVDP2","url":"https://www.omim.org/entry/620067"},{"mim_id":"616642","title":"CHROMOSOME 6 OPEN READING FRAME 89; C6ORF89","url":"https://www.omim.org/entry/616642"},{"mim_id":"615587","title":"NUCLEOPORIN, 188-KD; NUP188","url":"https://www.omim.org/entry/615587"},{"mim_id":"614951","title":"HEAT REPEAT-CONTAINING PROTEIN 3; HEATR3","url":"https://www.omim.org/entry/614951"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Cytoplasmic bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TNPO1"},"hgnc":{"alias_symbol":["MIP","TRN","IPO2","MIP1"],"prev_symbol":["KPNB2"]},"alphafold":{"accession":"Q92973","domains":[{"cath_id":"1.25.10","chopping":"720-898","consensus_level":"medium","plddt":94.8025,"start":720,"end":898}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92973","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92973-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92973-F1-predicted_aligned_error_v6.png","plddt_mean":92.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNPO1","jax_strain_url":"https://www.jax.org/strain/search?query=TNPO1"},"sequence":{"accession":"Q92973","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92973.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92973/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92973"}},"corpus_meta":[{"pmid":"28974576","id":"PMC_28974576","title":"MicroRNA miR-128 represses LINE-1 (L1) retrotransposition by down-regulating the nuclear import factor TNPO1.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28974576","citation_count":27,"is_preprint":false},{"pmid":"30269354","id":"PMC_30269354","title":"Potentially critical roles of TNPO1, RAP1B, ZDHHC17, and PPM1B in the progression of coronary atherosclerosis through microarray data analysis.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30269354","citation_count":20,"is_preprint":false},{"pmid":"33987449","id":"PMC_33987449","title":"TNPO1-Mediated Nuclear Import of FUBP1 Contributes to Tumor Immune Evasion by Increasing NRP1 Expression in Cervical Cancer.","date":"2021","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/33987449","citation_count":14,"is_preprint":false},{"pmid":"34044070","id":"PMC_34044070","title":"TNPO1-mediated nuclear import of ARID1B promotes tumor growth in ARID1A-deficient gynecologic cancer.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34044070","citation_count":11,"is_preprint":false},{"pmid":"32553752","id":"PMC_32553752","title":"Redox-dependent PPARγ/Tnpo1 complex formation enhances PPARγ nuclear localization and signaling.","date":"2020","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32553752","citation_count":10,"is_preprint":false},{"pmid":"36907439","id":"PMC_36907439","title":"Rab8 and TNPO1 are ciliary transport adaptors for GTPase Arl13b by interacting with its RVEP motif containing ciliary targeting sequence.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36907439","citation_count":9,"is_preprint":false},{"pmid":"36672460","id":"PMC_36672460","title":"Heavy Ion-Responsive lncRNA EBLN3P Functions in the Radiosensitization of Non-Small Cell Lung Cancer Cells Mediated by TNPO1.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36672460","citation_count":7,"is_preprint":false},{"pmid":"35388333","id":"PMC_35388333","title":"Role of miR-181b/Notch1 Axis in circ_TNPO1 Promotion of Proliferation and Migration of Atherosclerotic Vascular Smooth Muscle Cells.","date":"2022","source":"Journal of healthcare engineering","url":"https://pubmed.ncbi.nlm.nih.gov/35388333","citation_count":5,"is_preprint":false},{"pmid":"40216011","id":"PMC_40216011","title":"CircBRWD1 promotes hepatitis B virus replication and hepatocellular carcinoma progression by regulating the miR-513a-5p/TNPO1 axis.","date":"2025","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40216011","citation_count":1,"is_preprint":false},{"pmid":"42036045","id":"PMC_42036045","title":"Rab8 and TNPO1 function as the ciliary transport adapters for GPCRs.","date":"2026","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42036045","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6997,"output_tokens":1691,"usd":0.023178,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8514,"output_tokens":2327,"usd":0.050373,"stage2_stop_reason":"end_turn"},"total_usd":0.073551,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"TNPO1 (transportin-1) mediates nuclear import of the LINE-1 ribonucleoprotein complex (using ORF1p as a proxy); induction or depletion of TNPO1 directly affects L1 retrotransposition and nuclear import of the L1-RNP, and TNPO1 overexpression partially reverses the repressive effect of miR-128 on L1 retrotransposition.\",\n      \"method\": \"Overexpression and knockdown of TNPO1 combined with L1 retrotransposition reporter assay and nuclear import assay for ORF1p\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain- and loss-of-function experiments with specific phenotypic readout (retrotransposition and nuclear import), single lab, two orthogonal functional assays\",\n      \"pmids\": [\"28974576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TNPO1 mediates nuclear import of FUBP1 (far upstream element binding protein 1) in cervical cancer cells; FUBP1 physically interacts with TNPO1, and nuclear localization of FUBP1 — dependent on this interaction — drives transcriptional regulation of the immune checkpoint gene NRP1.\",\n      \"method\": \"Co-immunoprecipitation (FUBP1–TNPO1 interaction), knockdown experiments, subcellular fractionation, and gene expression analysis of NRP1\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP interaction plus functional knockdown with downstream gene expression phenotype, single lab\",\n      \"pmids\": [\"33987449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TNPO1 selectively mediates nuclear import of ARID1B in gynecologic cancer cells; loss of TNPO1 or ARID1B reduces chromatin accessibility, depletes H3K4me1 and H3K27ac histone marks, diminishes AP-1 transcription factor activity, and inactivates PI3K/AKT signaling by reducing PIK3CA and FGFR2 expression.\",\n      \"method\": \"Genetic knockdown (in vitro and in vivo xenograft), chromatin accessibility assay (ATAC-seq implied), ChIP for histone marks, gene expression profiling\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal downstream readouts (chromatin, histone marks, signaling pathway), single lab\",\n      \"pmids\": [\"34044070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PPARγ2 forms a redox-dependent complex with Tnpo1 via disulfide bonds between Cys176/Cys180 of PPARγ2 and Cys512 of Tnpo1; H2O2-driven complex formation enhances nuclear translocation of PPARγ2, increases DNA-bound PPARγ, and promotes downstream signaling leading to hepatic triglyceride accumulation.\",\n      \"method\": \"Co-immunoprecipitation, cysteine mutagenesis, hepatocyte culture overexpression/knockdown, mouse models, subcellular fractionation\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-IP with mutagenesis identifying specific cysteine residues, functional validation in both cell culture and mouse models, multiple orthogonal methods in one study\",\n      \"pmids\": [\"32553752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TNPO1 directly binds the ciliary targeting sequence (CTS) of Arl13b — a C-terminal 17-amino-acid stretch containing the RVEP motif — together with Rab8-GDP (but not Rab8-GTP); Rab8-GDP substantially enhances TNPO1–CTS interaction, and knockdown of endogenous TNPO1 decreases ciliary localization of Arl13b.\",\n      \"method\": \"Pull-down assays with cell lysates and purified recombinant proteins, TurboID-based proximity ligation, RVEP point-mutation analysis, siRNA knockdown with ciliary imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins, mutagenesis of the RVEP motif, proximity ligation, and knockdown phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"36907439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TNPO1, together with Rab8, functions as a ciliary transport adapter for multiple cilium-localized GPCRs; for β2 adrenergic receptor, TNPO1 and Rab8 interact specifically with the C-terminal CTS (not the third intracellular loop CTS), and both adapters are required for ciliary localization of this GPCR.\",\n      \"method\": \"Pull-down interaction screening of nine ciliary GPCRs, CTS truncation/mutation mapping, siRNA knockdown of Rab8 and TNPO1 with ciliary localization readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic interaction screen with mutagenesis and knockdown phenotype, single lab, extends prior reconstitution work\",\n      \"pmids\": [\"42036045\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNPO1 (transportin-1/karyopherin-β2) is a nuclear and ciliary import receptor that recognizes diverse cargoes — including LINE-1 RNPs, FUBP1, ARID1B, and PPARγ2 (the latter via redox-sensitive disulfide bonds involving Cys512) — to mediate their nuclear translocation, and also functions together with Rab8-GDP as a ciliary transport adapter for Arl13b and multiple GPCRs by binding RVEP-containing ciliary targeting sequences.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TNPO1 (transportin-1) is a soluble nuclear/ciliary import receptor that recognizes diverse cargoes through dedicated targeting determinants to direct their subcellular localization [#3, #4]. In its classic nuclear-import role it mediates translocation of multiple cargoes, including the LINE-1 ribonucleoprotein (where TNPO1 levels set the rate of L1 retrotransposition) [#0], FUBP1 (whose TNPO1-dependent nuclear accumulation drives transcription of the immune checkpoint gene NRP1) [#1], and the chromatin remodeler ARID1B (loss of which reduces chromatin accessibility, depletes H3K4me1/H3K27ac, and impairs AP-1 and PI3K/AKT signaling) [#2]. Cargo engagement can be redox-gated: TNPO1 forms an H2O2-induced disulfide complex with PPARγ2 via Cys512 of TNPO1 and Cys176/Cys180 of PPARγ2, enhancing PPARγ2 nuclear entry and promoting hepatic triglyceride accumulation [#3]. Beyond the nucleus, TNPO1 acts as a ciliary transport adapter: together with Rab8-GDP it binds RVEP-motif ciliary targeting sequences to deliver Arl13b and multiple GPCRs, including the β2 adrenergic receptor, to the cilium, with Rab8-GDP strongly enhancing recognition of the targeting sequence [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established TNPO1 as the import factor controlling nuclear entry of the LINE-1 RNP, linking it to retrotransposon mobility rather than only canonical protein cargoes.\",\n      \"evidence\": \"TNPO1 overexpression/knockdown with L1 retrotransposition reporter and ORF1p nuclear import assays\",\n      \"pmids\": [\"28974576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the targeting motif on the L1-RNP recognized by TNPO1\", \"Whether TNPO1 binds ORF1p directly or via another adaptor is not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that TNPO1 cargo recognition can be redox-regulated, identifying a specific disulfide interface (TNPO1 Cys512 with PPARγ2 Cys176/Cys180) that couples oxidative state to nuclear import.\",\n      \"evidence\": \"Co-IP, cysteine mutagenesis, hepatocyte overexpression/knockdown, and mouse models\",\n      \"pmids\": [\"32553752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether redox gating applies to other TNPO1 cargoes is untested\", \"Structural basis of the disulfide-stabilized complex is not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended TNPO1 cargo repertoire to transcription/chromatin regulators (FUBP1 and ARID1B), connecting its import function to downstream transcriptional and chromatin outputs in cancer.\",\n      \"evidence\": \"Co-IP, knockdown, subcellular fractionation, chromatin accessibility and ChIP assays in cancer cells\",\n      \"pmids\": [\"33987449\", \"34044070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Targeting sequences on FUBP1 and ARID1B recognized by TNPO1 are not mapped\", \"Cargo selectivity versus other karyopherins is not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-nuclear function: TNPO1 acts with Rab8-GDP as a ciliary transport adapter that recognizes an RVEP-containing ciliary targeting sequence on Arl13b.\",\n      \"evidence\": \"Pull-downs with purified proteins, TurboID proximity ligation, RVEP point mutagenesis, and siRNA with ciliary imaging\",\n      \"pmids\": [\"36907439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a nuclear import receptor is repurposed for ciliary delivery is unclear\", \"How Rab8 nucleotide state is coordinated with cargo handoff at the cilium is unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Generalized the ciliary adapter role, showing TNPO1/Rab8 recognize C-terminal CTSs of multiple ciliary GPCRs and are required for their ciliary localization.\",\n      \"evidence\": \"Interaction screening of nine ciliary GPCRs, CTS truncation/mutation mapping, and Rab8/TNPO1 siRNA with ciliary localization readout\",\n      \"pmids\": [\"42036045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Consensus features defining a TNPO1-recognized ciliary CTS are not fully defined\", \"In vitro reconstitution with purified GPCR CTSs is not reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how TNPO1 partitions between nuclear-import and ciliary-adapter functions and what structural determinants distinguish nuclear targeting signals from RVEP ciliary targeting sequences.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of TNPO1 cargo recognition across nuclear and ciliary cargoes\", \"Regulation of TNPO1 localization and function across compartments is uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008565\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB8A\", \"ARL13B\", \"PPARG\", \"FUBP1\", \"ARID1B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}