{"gene":"LZTFL1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2011,"finding":"LZTFL1 physically interacts with the BBSome protein complex and negatively regulates ciliary trafficking of the BBSome; all BBSome subunits and BBS3 (ARL6) are required for BBSome ciliary entry; reduction of LZTFL1 restores BBSome trafficking to cilia in BBS3- and BBS5-depleted cells; BBS proteins and LZTFL1 regulate ciliary trafficking of the Hedgehog signal transducer Smoothened.","method":"Co-immunoprecipitation, siRNA knockdown, fluorescence microscopy of ciliary localization, genetic epistasis in cell lines","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, epistasis via double knockdowns, direct ciliary localization imaging; replicated in subsequent studies","pmids":["22072986"],"is_preprint":false},{"year":2012,"finding":"Loss of LZTFL1 in patient fibroblasts results in a significant increase in ciliary Smoothened (Smo) and upregulation of Patched1 and downstream target GLI2, demonstrating that LZTFL1 acts as a negative regulator of the Sonic Hedgehog (Shh) signaling pathway.","method":"Immunofluorescence and protein expression analysis in patient-derived fibroblasts with homozygous LZTFL1 deletion","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional cellular readout in patient fibroblasts, single study","pmids":["22510444"],"is_preprint":false},{"year":2014,"finding":"LZTFL1 binds β-catenin in the cytoplasm and inhibits its nuclear translocation, thereby suppressing EMT, cell migration, invasion, and MMP activity in gastric cancer cells.","method":"Co-immunoprecipitation, Duolink in situ proximity ligation assay, Transwell migration/invasion assay, gelatin zymography, LZTFL1 knockdown/overexpression","journal":"Journal of cancer research and clinical oncology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus proximity ligation plus functional cellular assays, multiple orthogonal methods in one study","pmids":["25005785"],"is_preprint":false},{"year":2015,"finding":"LZTFL1 inhibits TGF-β-activated MAPK signaling and Hedgehog signaling in lung epithelial cells; alteration of LZTFL1 levels changes expression of EMT-associated genes; re-expression of LZTFL1 in lung tumor cells inhibits extravasation/colonization in vivo.","method":"LZTFL1 knockdown/re-expression in NSCLC lines, Western blotting for pathway components, in vivo mouse colonization assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — KO/OE with defined pathway readouts and in vivo validation, single lab","pmids":["26364604"],"is_preprint":false},{"year":2015,"finding":"LZTFL1 accumulates at the plasma membrane of CD4+ T cells and transiently redistributes to the immunological synapse during T cell–APC contact; LZTFL1 knockdown reduces IL-5 production and overexpression enhances TCR-mediated NFAT signaling, indicating LZTFL1 is a regulator of T cell activation downstream of TCR signaling.","method":"Live-cell imaging, immunofluorescence, siRNA knockdown, LZTFL1 overexpression, NFAT reporter assay, cytokine ELISA","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional consequence, multiple orthogonal methods, single lab","pmids":["26700766"],"is_preprint":false},{"year":2016,"finding":"In Lztfl1 knockout mice, LZTFL1 localizes to the primary cilium of kidney cells; absence of LZTFL1 increases ciliary localization of BBS9; in retinal photoreceptors, loss of LZTFL1 causes shortening of the outer segment, enlargement of the connecting cilium distal axoneme, mislocalization of rhodopsin to the outer nuclear layer, and photoreceptor apoptosis; LZTFL1 depletion also causes abnormal accumulation of adaptor protein complex 1 (AP1) in photoreceptor cells.","method":"Lztfl1 knockout mouse model, immunofluorescence, TUNEL assay, electron microscopy, subcellular fractionation","journal":"Journal of genetics and genomics","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multiple defined cellular phenotypes and direct localization experiments, orthogonal methods","pmids":["27312011"],"is_preprint":false},{"year":2018,"finding":"Lztfl1 knockout mice are hyperphagic and leptin-resistant; inactivation of Lztfl1 abolishes STAT3 phosphorylation in the hypothalamic leptin receptor (LepRb) signaling pathway upon leptin stimulation without affecting LepRb membrane localization; the obese phenotype requires loss of Lztfl1 in brain (not adipocytes); Lztfl1-/- MEFs have significantly longer cilia; Lztfl1 interacts with proteins involved in actin/cytoskeleton dynamics.","method":"Conditional Lztfl1 knockout mouse, phospho-STAT3 Western blotting, leptin stimulation assay, tissue-specific deletion, primary cilia length measurement, Co-IP interactome","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with pathway-specific molecular readout (pSTAT3), multiple orthogonal experiments in one study","pmids":["30423168"],"is_preprint":false},{"year":2019,"finding":"miR-21 directly targets the 3′ UTR of LZTFL1 mRNA (confirmed by luciferase reporter assay) to suppress LZTFL1 expression; LZTFL1 knockdown overcomes the inhibitory effect of miR-21 inhibitor on breast cancer cell proliferation, metastasis, and EMT marker expression, placing LZTFL1 downstream of miR-21 in the miR-21–LZTFL1–EMT axis.","method":"Luciferase 3′ UTR reporter assay, siRNA knockdown, colony formation, Transwell and wound-healing assays, in vivo mouse tumor model","journal":"BMC cancer","confidence":"High","confidence_rationale":"Tier 1/2 — luciferase reporter validates direct miR-21 targeting, epistasis by co-transfection, in vivo validation; highly cited","pmids":["31351450"],"is_preprint":false},{"year":2021,"finding":"In Chlamydomonas, LZTFL1 maintains BBSome ciliary dynamics by dual control: (1) promoting basal body targeting of BBS3 (ARL6 GTPase) to control BBSome loading onto anterograde IFT trains for ciliary entry, and (2) stabilizing IFT25/27 in the cell body to promote BBSome reassembly at the ciliary tip for loading onto retrograde IFT trains for ciliary exit; LZTFL1 loss deprives the BBSome of ciliary presence and causes defective phototaxis.","method":"Chlamydomonas LZTFL1 mutant analysis, fluorescence microscopy of BBSome and IFT component localization, phototaxis behavioral assay, genetic rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection in ortholog with multiple imaging-based experiments, genetic epistasis, behavioral readout","pmids":["34446551"],"is_preprint":false},{"year":2021,"finding":"LZTFL1 is required for normal sperm flagella structure and male fertility; global Lztfl1 knockout leads to asthenoteratozoospermia; LZTFL1 is expressed in spermiogenesis and localizes to developing sperm flagella and near the manchette; loss of LZTFL1 specifically reduces testicular IFT27 protein levels without affecting IFT20, IFT81, IFT88, or IFT140, demonstrating a selective role for LZTFL1 in maintaining IFT27 stability during spermatogenesis.","method":"Lztfl1 knockout mouse, sperm motility analysis, in vitro fertilization assay, Western blotting, immunofluorescence localization","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined cellular phenotype, specific IFT27 molecular mechanism, multiple orthogonal methods","pmids":["34023333"],"is_preprint":false},{"year":2021,"finding":"A gain-of-function risk A allele at SNP rs17713054 acts through an enhancer to upregulate LZTFL1 expression in lung epithelial cells (established by chromosome conformation capture and gene expression analysis); spatial transcriptomic analysis of COVID-19 lung biopsies links upregulated LZTFL1 to EMT-related viral response pathways in pulmonary epithelial cells.","method":"Chromosome conformation capture (3C/Hi-C), gene expression analysis, spatial transcriptomics of patient lung biopsies, multiomics + machine learning","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1/2 — chromosome conformation capture plus spatial transcriptomics plus multiomics, multiple orthogonal approaches in one study","pmids":["34737427"],"is_preprint":false},{"year":2021,"finding":"SNHG6 lncRNA promotes LZTFL1 mRNA destabilization via the SNHG6–PTBP1 complex, which facilitates degradation of LZTFL1 mRNA in hepatoma cells; silencing LZTFL1 reverses the suppressive effect of SNHG6 knockdown on HCC progression, placing LZTFL1 downstream of the SNHG6–PTBP1 axis in post-transcriptional regulation.","method":"Quantitative proteomics, RNA immunoprecipitation, siRNA knockdown, mRNA stability assays, epistasis rescue experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — MS-identified interaction, mRNA stability assay, epistasis, single lab","pmids":["34252487"],"is_preprint":false},{"year":2022,"finding":"CRISPRi targeting of a region near rs11385942 at chromosome 3p21.31 (intron 5 of LZTFL1) significantly reduces LZTFL1 expression in lung epithelial cell lines, demonstrating that this COVID-19 GWAS locus functionally regulates LZTFL1 transcription in airway cells.","method":"CRISPRi-mediated gene expression knockdown in lung epithelial cell lines, qRT-PCR","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPRi is a direct functional experiment; single lab, single method","pmids":["34998241"],"is_preprint":false},{"year":2023,"finding":"LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through the ZNRF1-mediated ubiquitin proteasome pathway, inducing G1 cell cycle arrest; this was validated in kidney tumor cell lines and a patient-derived xenograft (PDX) model.","method":"LZTFL1 gain- and loss-of-function in ccRCC cell lines, Western blotting for AKT ubiquitination and stability, co-immunoprecipitation with ZNRF1, PDX lentiviral overexpression, flow cytometry cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional methods including PDX in vivo validation and Co-IP for ZNRF1 interaction, single lab","pmids":["36966254"],"is_preprint":false},{"year":2024,"finding":"In LZTFL1-depleted mouse mesenchymal stem cells (CB-MSCs), Wnt/β-catenin signaling is inhibited: total β-catenin is reduced, LRP6 (Wnt co-receptor) is elevated at the cell surface and lipid rafts, and caveolin-1 (CAV1, required for LRP6-mediated Wnt activation) is reduced; this leads to increased nuclear glucocorticoid receptor and PPARγ, promoting enhanced adipogenesis.","method":"Lztfl1 knockout mouse, CB-MSC isolation and differentiation assay, Western blotting, flow cytometry, lipid raft fractionation, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — KO-derived primary cells with multiple pathway component analyses, single lab","pmids":["39662832"],"is_preprint":false},{"year":2011,"finding":"Overexpression of Lztfl1 in Neuro 2a neuronal cells promotes neurite outgrowth, indicating a role for LZTFL1 in neuronal differentiation.","method":"Lztfl1 overexpression in Neuro 2a cells, morphological analysis of neurite length","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single overexpression experiment, no mechanistic pathway identified, single lab","pmids":["22093827"],"is_preprint":false}],"current_model":"LZTFL1 is a ciliary regulatory protein that acts as a negative regulator of BBSome ciliary trafficking by controlling BBS3-dependent BBSome loading at the basal body and IFT25/27-dependent BBSome reassembly at the ciliary tip, thereby governing Smoothened/Hedgehog signaling; in non-ciliary contexts it suppresses EMT by sequestering β-catenin in the cytoplasm, destabilizes AKT via the ZNRF1 ubiquitin-proteasome pathway, and regulates leptin receptor (LepRb)–STAT3 signaling in hypothalamic neurons to control energy homeostasis, while its expression is post-transcriptionally suppressed by miR-21 and the SNHG6–PTBP1 complex."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing that LZTFL1 is a physical interactor and negative regulator of BBSome ciliary trafficking resolved how the BBSome is restrained from constitutive ciliary entry and linked LZTFL1 to Hedgehog/Smoothened signaling.","evidence":"Co-immunoprecipitation, siRNA epistasis, and fluorescence microscopy of ciliary localization in mammalian cell lines","pmids":["22072986"],"confidence":"High","gaps":["Mechanism by which LZTFL1 physically restrains BBSome at the basal body not resolved","Whether LZTFL1 acts catalytically or as a stoichiometric scaffold unclear","In vivo consequence of LZTFL1–BBSome interaction not yet tested in animal models"]},{"year":2012,"claim":"Patient fibroblasts with homozygous LZTFL1 deletion confirmed that LZTFL1 loss causes elevated ciliary Smoothened and activation of Hedgehog targets, establishing LZTFL1 as a disease-relevant negative regulator of Shh signaling in human cells.","evidence":"Immunofluorescence and protein expression analysis in patient-derived LZTFL1-null fibroblasts","pmids":["22510444"],"confidence":"Medium","gaps":["Based on a single patient genotype; broader patient cohort not examined","Downstream transcriptional consequences (GLI target gene panel) not comprehensively profiled"]},{"year":2014,"claim":"Discovery that LZTFL1 binds β-catenin cytoplasmically and prevents its nuclear translocation revealed a non-ciliary tumor-suppressive mechanism through EMT inhibition.","evidence":"Co-immunoprecipitation, proximity ligation assay, and Transwell migration/invasion assays in gastric cancer cells","pmids":["25005785"],"confidence":"High","gaps":["Whether LZTFL1–β-catenin binding is direct or mediated by an adaptor not resolved","Structural basis of the interaction unknown"]},{"year":2015,"claim":"Demonstration that LZTFL1 inhibits TGF-β–MAPK and Hedgehog signaling in lung epithelium and suppresses tumor colonization in vivo broadened its EMT-suppressive role beyond gastric to lung cancer.","evidence":"LZTFL1 knockdown/re-expression in NSCLC lines with pathway Western blots and mouse colonization assay","pmids":["26364604"],"confidence":"Medium","gaps":["Whether LZTFL1 directly engages TGF-β receptor components or acts indirectly not determined","Single-lab in vivo colonization model"]},{"year":2016,"claim":"Lztfl1 knockout mice revealed in vivo ciliary functions: LZTFL1 localizes to primary cilia, restrains BBS9 ciliary accumulation, and is essential for photoreceptor outer segment integrity, connecting BBSome regulation to retinal degeneration.","evidence":"Lztfl1 knockout mouse with immunofluorescence, electron microscopy, TUNEL assay, and subcellular fractionation in kidney and retina","pmids":["27312011"],"confidence":"High","gaps":["Mechanism linking LZTFL1 loss to AP1 mislocalization in photoreceptors not elucidated","Whether photoreceptor degeneration is cell-autonomous not fully resolved"]},{"year":2018,"claim":"Conditional knockout studies showed LZTFL1 is required in hypothalamic neurons for leptin-stimulated STAT3 phosphorylation and energy homeostasis, establishing a brain-specific metabolic function independent of adipocyte LZTFL1.","evidence":"Conditional Lztfl1 knockout mouse with tissue-specific deletion, phospho-STAT3 immunoblotting, and leptin stimulation","pmids":["30423168"],"confidence":"High","gaps":["Molecular step at which LZTFL1 enables LepRb–STAT3 coupling not identified","Whether the metabolic phenotype is cilium-dependent or cilium-independent not distinguished"]},{"year":2019,"claim":"Identification of miR-21 as a direct post-transcriptional repressor of LZTFL1 defined an upstream regulatory axis (miR-21→LZTFL1→EMT) in breast cancer.","evidence":"Luciferase 3′ UTR reporter assay, epistasis by co-transfection, in vivo mouse tumor model","pmids":["31351450"],"confidence":"High","gaps":["Whether other miRNAs redundantly target LZTFL1 not explored","Tissue specificity of miR-21 regulation of LZTFL1 not addressed"]},{"year":2021,"claim":"Mechanistic dissection in Chlamydomonas resolved LZTFL1's dual control over BBSome dynamics: promoting BBS3-dependent anterograde loading at the basal body and stabilizing IFT25/27 for retrograde reassembly at the ciliary tip.","evidence":"Chlamydomonas LZTFL1 mutant with BBSome/IFT fluorescence microscopy, genetic rescue, and phototaxis behavioral assay","pmids":["34446551"],"confidence":"High","gaps":["Whether the dual-control model fully applies in mammalian cilia not confirmed","Biochemical basis of LZTFL1-dependent IFT25/27 stabilization unknown"]},{"year":2021,"claim":"LZTFL1 was shown to selectively stabilize IFT27 during spermatogenesis; its loss causes asthenoteratozoospermia and male infertility, extending the IFT-stabilization mechanism to mammalian motile cilia/flagella.","evidence":"Lztfl1 knockout mouse sperm analysis, IFT protein Western blots, in vitro fertilization assay","pmids":["34023333"],"confidence":"High","gaps":["Whether IFT27 instability is the sole cause of flagellar defects not determined","Rescue by IFT27 re-expression not performed"]},{"year":2021,"claim":"The COVID-19 risk allele rs17713054 was functionally linked to LZTFL1 upregulation in lung epithelium through an enhancer, connecting LZTFL1 expression levels to severe COVID-19 via EMT-related pathways.","evidence":"Chromosome conformation capture, gene expression analysis, and spatial transcriptomics of COVID-19 lung biopsies","pmids":["34737427","34998241"],"confidence":"High","gaps":["Whether LZTFL1 overexpression directly impairs antiviral defense or acts through EMT-related barrier disruption not resolved","Causal rescue experiments (LZTFL1 normalization in risk-allele cells) not reported"]},{"year":2023,"claim":"Discovery that LZTFL1 destabilizes AKT through ZNRF1-mediated ubiquitination defined a non-ciliary tumor-suppressive mechanism distinct from β-catenin sequestration, causing G1 arrest in kidney cancer.","evidence":"LZTFL1 gain/loss-of-function in ccRCC cell lines, Co-IP with ZNRF1, AKT ubiquitination assays, PDX model","pmids":["36966254"],"confidence":"Medium","gaps":["Whether LZTFL1 acts as a scaffold bridging ZNRF1 to AKT or has a separate role not resolved","Generalizability beyond ccRCC not tested"]},{"year":2024,"claim":"In Lztfl1 KO mesenchymal stem cells, Wnt/β-catenin signaling is paradoxically inhibited—with reduced total β-catenin and caveolin-1—leading to enhanced adipogenesis, revealing a context-dependent role for LZTFL1 in Wnt pathway modulation.","evidence":"Lztfl1 knockout mouse CB-MSC differentiation assays, lipid raft fractionation, Western blotting, flow cytometry","pmids":["39662832"],"confidence":"Medium","gaps":["Apparent contradiction with gastric cancer data (where LZTFL1 loss activates β-catenin) not mechanistically reconciled","Whether caveolin-1 reduction is a direct or indirect consequence of LZTFL1 loss unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis of LZTFL1's interaction with the BBSome and β-catenin, whether its ciliary and non-ciliary functions are mechanistically separable, and how tissue context determines whether LZTFL1 loss activates or inhibits Wnt/β-catenin signaling.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal or cryo-EM structure of LZTFL1 or its complexes available","Separation-of-function mutants distinguishing ciliary from EMT roles not generated","Reconciliation of opposing β-catenin outcomes in different cell types not achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3,6,14]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,5,8,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,9]}],"complexes":["BBSome"],"partners":["BBS3","BBS5","BBS9","IFT27","CTNNB1","ZNRF1","PTBP1"],"other_free_text":[]},"mechanistic_narrative":"LZTFL1 is a cytoplasmic regulatory protein that governs ciliary trafficking of the BBSome and modulates epithelial-to-mesenchymal transition (EMT) signaling in multiple tissue contexts. It physically interacts with the BBSome complex and controls BBSome ciliary entry and exit by promoting BBS3 (ARL6) targeting to the basal body and stabilizing IFT25/27 for retrograde transport; loss of LZTFL1 disrupts Smoothened/Hedgehog signaling, photoreceptor outer segment integrity, and sperm flagella formation [PMID:22072986, PMID:34446551, PMID:27312011, PMID:34023333]. In non-ciliary contexts, LZTFL1 suppresses EMT by sequestering β-catenin in the cytoplasm to prevent its nuclear translocation, destabilizes AKT through ZNRF1-mediated ubiquitin-proteasome degradation to induce cell cycle arrest, and is required in hypothalamic neurons for leptin receptor–STAT3 signaling and energy homeostasis [PMID:25005785, PMID:36966254, PMID:30423168]. The COVID-19 risk allele rs17713054 upregulates LZTFL1 expression in lung epithelial cells via an enhancer element, linking increased LZTFL1 to EMT-associated pulmonary pathology [PMID:34737427, PMID:34998241]."},"prefetch_data":{"uniprot":{"accession":"Q9NQ48","full_name":"Leucine zipper transcription factor-like protein 1","aliases":[],"length_aa":299,"mass_kda":34.6,"function":"Regulates ciliary localization of the BBSome complex. Together with the BBSome complex, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. May play a role in neurite outgrowth. May have tumor suppressor function","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NQ48/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LZTFL1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LZTFL1","total_profiled":1310},"omim":[{"mim_id":"615994","title":"BARDET-BIEDL SYNDROME 17; BBS17","url":"https://www.omim.org/entry/615994"},{"mim_id":"608132","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 8; TTC8","url":"https://www.omim.org/entry/608132"},{"mim_id":"607968","title":"PARATHYROID HORMONE-RESPONSIVE B1 GENE","url":"https://www.omim.org/entry/607968"},{"mim_id":"607590","title":"BBS7 GENE; BBS7","url":"https://www.omim.org/entry/607590"},{"mim_id":"606569","title":"SAC1-LIKE PHOSPHATIDYLINOSITIDE PHOSPHATASE; SACM1L","url":"https://www.omim.org/entry/606569"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium transition zone","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LZTFL1"},"hgnc":{"alias_symbol":["BBS17"],"prev_symbol":[]},"alphafold":{"accession":"Q9NQ48","domains":[{"cath_id":"-","chopping":"9-127","consensus_level":"high","plddt":89.9966,"start":9,"end":127},{"cath_id":"1.20.5","chopping":"269-299","consensus_level":"medium","plddt":75.5426,"start":269,"end":299}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ48","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ48-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ48-F1-predicted_aligned_error_v6.png","plddt_mean":83.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LZTFL1","jax_strain_url":"https://www.jax.org/strain/search?query=LZTFL1"},"sequence":{"accession":"Q9NQ48","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NQ48.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NQ48/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ48"}},"corpus_meta":[{"pmid":"31351450","id":"PMC_31351450","title":"microRNA-21 promotes breast cancer proliferation and metastasis by targeting LZTFL1.","date":"2019","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31351450","citation_count":213,"is_preprint":false},{"pmid":"22072986","id":"PMC_22072986","title":"A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22072986","citation_count":164,"is_preprint":false},{"pmid":"34737427","id":"PMC_34737427","title":"Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus.","date":"2021","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34737427","citation_count":112,"is_preprint":false},{"pmid":"22510444","id":"PMC_22510444","title":"Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet--Biedl syndrome with situs inversus and insertional polydactyly.","date":"2012","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22510444","citation_count":102,"is_preprint":false},{"pmid":"26364604","id":"PMC_26364604","title":"LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/26364604","citation_count":43,"is_preprint":false},{"pmid":"23692385","id":"PMC_23692385","title":"Mesoaxial polydactyly is a major feature in Bardet-Biedl syndrome patients with LZTFL1 (BBS17) mutations.","date":"2013","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23692385","citation_count":31,"is_preprint":false},{"pmid":"11352561","id":"PMC_11352561","title":"The LZTFL1 gene is a part of a transcriptional map covering 250 kb within the common eliminated region 1 (C3CER1) in 3p21.3.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11352561","citation_count":31,"is_preprint":false},{"pmid":"27312011","id":"PMC_27312011","title":"Depletion of BBS Protein LZTFL1 Affects Growth and Causes Retinal Degeneration in Mice.","date":"2016","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/27312011","citation_count":30,"is_preprint":false},{"pmid":"25005785","id":"PMC_25005785","title":"LZTFL1 suppresses gastric cancer cell migration and invasion through regulating nuclear translocation of β-catenin.","date":"2014","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25005785","citation_count":30,"is_preprint":false},{"pmid":"26700766","id":"PMC_26700766","title":"LZTFL1 Upregulated by All-Trans Retinoic Acid during CD4+ T Cell Activation Enhances IL-5 Production.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26700766","citation_count":27,"is_preprint":false},{"pmid":"34252487","id":"PMC_34252487","title":"lncRNA SNHG6 promotes hepatocellular carcinoma progression by interacting with HNRNPL/PTBP1 to facilitate SETD7/LZTFL1 mRNA destabilization.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34252487","citation_count":27,"is_preprint":false},{"pmid":"34998241","id":"PMC_34998241","title":"CRISPRi links COVID-19 GWAS loci to LZTFL1 and RAVER1.","date":"2022","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/34998241","citation_count":21,"is_preprint":false},{"pmid":"30423168","id":"PMC_30423168","title":"Lztfl1/BBS17 controls energy homeostasis by regulating the leptin signaling in the hypothalamic neurons.","date":"2018","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30423168","citation_count":20,"is_preprint":false},{"pmid":"35753602","id":"PMC_35753602","title":"Host genetic loci LZTFL1 and CCL2 associated with SARS-CoV-2 infection and severity of COVID-19.","date":"2022","source":"International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/35753602","citation_count":17,"is_preprint":false},{"pmid":"34446551","id":"PMC_34446551","title":"Chlamydomonas LZTFL1 mediates phototaxis via controlling BBSome recruitment to the basal body and its reassembly at the ciliary tip.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34446551","citation_count":17,"is_preprint":false},{"pmid":"34023333","id":"PMC_34023333","title":"Leucine zipper transcription factor-like 1 (LZTFL1), an intraflagellar transporter 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LZTFL1 Polymorphisms and Risk of COVID-19 in the Czech Population.","date":"2023","source":"Physiological research","url":"https://pubmed.ncbi.nlm.nih.gov/37795896","citation_count":5,"is_preprint":false},{"pmid":"37424811","id":"PMC_37424811","title":"lncRNA ASBEL and lncRNA Erbb4-IR reduce chemoresistance against gemcitabine and cisplatin in stage IV lung squamous cell carcinoma via the microRNA-21/LZTFL1 axis.","date":"2023","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/37424811","citation_count":5,"is_preprint":false},{"pmid":"36966254","id":"PMC_36966254","title":"LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36966254","citation_count":4,"is_preprint":false},{"pmid":"38310669","id":"PMC_38310669","title":"Anti-inflammation of LZTFL1 knockdown in OVA-induced asthmatic mice: Through ERK/GATA3 signaling 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all BBSome subunits and BBS3 (ARL6) are required for BBSome ciliary entry; reduction of LZTFL1 restores BBSome trafficking to cilia in BBS3- and BBS5-depleted cells; BBS proteins and LZTFL1 regulate ciliary trafficking of the Hedgehog signal transducer Smoothened.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, fluorescence microscopy of ciliary localization, genetic epistasis in cell lines\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, epistasis via double knockdowns, direct ciliary localization imaging; replicated in subsequent studies\",\n      \"pmids\": [\"22072986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of LZTFL1 in patient fibroblasts results in a significant increase in ciliary Smoothened (Smo) and upregulation of Patched1 and downstream target GLI2, demonstrating that LZTFL1 acts as a negative regulator of the Sonic Hedgehog (Shh) signaling pathway.\",\n      \"method\": \"Immunofluorescence and protein expression analysis in patient-derived fibroblasts with homozygous LZTFL1 deletion\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cellular readout in patient fibroblasts, single study\",\n      \"pmids\": [\"22510444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LZTFL1 binds β-catenin in the cytoplasm and inhibits its nuclear translocation, thereby suppressing EMT, cell migration, invasion, and MMP activity in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, Duolink in situ proximity ligation assay, Transwell migration/invasion assay, gelatin zymography, LZTFL1 knockdown/overexpression\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus proximity ligation plus functional cellular assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25005785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LZTFL1 inhibits TGF-β-activated MAPK signaling and Hedgehog signaling in lung epithelial cells; alteration of LZTFL1 levels changes expression of EMT-associated genes; re-expression of LZTFL1 in lung tumor cells inhibits extravasation/colonization in vivo.\",\n      \"method\": \"LZTFL1 knockdown/re-expression in NSCLC lines, Western blotting for pathway components, in vivo mouse colonization assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO/OE with defined pathway readouts and in vivo validation, single lab\",\n      \"pmids\": [\"26364604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LZTFL1 accumulates at the plasma membrane of CD4+ T cells and transiently redistributes to the immunological synapse during T cell–APC contact; LZTFL1 knockdown reduces IL-5 production and overexpression enhances TCR-mediated NFAT signaling, indicating LZTFL1 is a regulator of T cell activation downstream of TCR signaling.\",\n      \"method\": \"Live-cell imaging, immunofluorescence, siRNA knockdown, LZTFL1 overexpression, NFAT reporter assay, cytokine ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26700766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Lztfl1 knockout mice, LZTFL1 localizes to the primary cilium of kidney cells; absence of LZTFL1 increases ciliary localization of BBS9; in retinal photoreceptors, loss of LZTFL1 causes shortening of the outer segment, enlargement of the connecting cilium distal axoneme, mislocalization of rhodopsin to the outer nuclear layer, and photoreceptor apoptosis; LZTFL1 depletion also causes abnormal accumulation of adaptor protein complex 1 (AP1) in photoreceptor cells.\",\n      \"method\": \"Lztfl1 knockout mouse model, immunofluorescence, TUNEL assay, electron microscopy, subcellular fractionation\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple defined cellular phenotypes and direct localization experiments, orthogonal methods\",\n      \"pmids\": [\"27312011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Lztfl1 knockout mice are hyperphagic and leptin-resistant; inactivation of Lztfl1 abolishes STAT3 phosphorylation in the hypothalamic leptin receptor (LepRb) signaling pathway upon leptin stimulation without affecting LepRb membrane localization; the obese phenotype requires loss of Lztfl1 in brain (not adipocytes); Lztfl1-/- MEFs have significantly longer cilia; Lztfl1 interacts with proteins involved in actin/cytoskeleton dynamics.\",\n      \"method\": \"Conditional Lztfl1 knockout mouse, phospho-STAT3 Western blotting, leptin stimulation assay, tissue-specific deletion, primary cilia length measurement, Co-IP interactome\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with pathway-specific molecular readout (pSTAT3), multiple orthogonal experiments in one study\",\n      \"pmids\": [\"30423168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-21 directly targets the 3′ UTR of LZTFL1 mRNA (confirmed by luciferase reporter assay) to suppress LZTFL1 expression; LZTFL1 knockdown overcomes the inhibitory effect of miR-21 inhibitor on breast cancer cell proliferation, metastasis, and EMT marker expression, placing LZTFL1 downstream of miR-21 in the miR-21–LZTFL1–EMT axis.\",\n      \"method\": \"Luciferase 3′ UTR reporter assay, siRNA knockdown, colony formation, Transwell and wound-healing assays, in vivo mouse tumor model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — luciferase reporter validates direct miR-21 targeting, epistasis by co-transfection, in vivo validation; highly cited\",\n      \"pmids\": [\"31351450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Chlamydomonas, LZTFL1 maintains BBSome ciliary dynamics by dual control: (1) promoting basal body targeting of BBS3 (ARL6 GTPase) to control BBSome loading onto anterograde IFT trains for ciliary entry, and (2) stabilizing IFT25/27 in the cell body to promote BBSome reassembly at the ciliary tip for loading onto retrograde IFT trains for ciliary exit; LZTFL1 loss deprives the BBSome of ciliary presence and causes defective phototaxis.\",\n      \"method\": \"Chlamydomonas LZTFL1 mutant analysis, fluorescence microscopy of BBSome and IFT component localization, phototaxis behavioral assay, genetic rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection in ortholog with multiple imaging-based experiments, genetic epistasis, behavioral readout\",\n      \"pmids\": [\"34446551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LZTFL1 is required for normal sperm flagella structure and male fertility; global Lztfl1 knockout leads to asthenoteratozoospermia; LZTFL1 is expressed in spermiogenesis and localizes to developing sperm flagella and near the manchette; loss of LZTFL1 specifically reduces testicular IFT27 protein levels without affecting IFT20, IFT81, IFT88, or IFT140, demonstrating a selective role for LZTFL1 in maintaining IFT27 stability during spermatogenesis.\",\n      \"method\": \"Lztfl1 knockout mouse, sperm motility analysis, in vitro fertilization assay, Western blotting, immunofluorescence localization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotype, specific IFT27 molecular mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"34023333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A gain-of-function risk A allele at SNP rs17713054 acts through an enhancer to upregulate LZTFL1 expression in lung epithelial cells (established by chromosome conformation capture and gene expression analysis); spatial transcriptomic analysis of COVID-19 lung biopsies links upregulated LZTFL1 to EMT-related viral response pathways in pulmonary epithelial cells.\",\n      \"method\": \"Chromosome conformation capture (3C/Hi-C), gene expression analysis, spatial transcriptomics of patient lung biopsies, multiomics + machine learning\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — chromosome conformation capture plus spatial transcriptomics plus multiomics, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"34737427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNHG6 lncRNA promotes LZTFL1 mRNA destabilization via the SNHG6–PTBP1 complex, which facilitates degradation of LZTFL1 mRNA in hepatoma cells; silencing LZTFL1 reverses the suppressive effect of SNHG6 knockdown on HCC progression, placing LZTFL1 downstream of the SNHG6–PTBP1 axis in post-transcriptional regulation.\",\n      \"method\": \"Quantitative proteomics, RNA immunoprecipitation, siRNA knockdown, mRNA stability assays, epistasis rescue experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified interaction, mRNA stability assay, epistasis, single lab\",\n      \"pmids\": [\"34252487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPRi targeting of a region near rs11385942 at chromosome 3p21.31 (intron 5 of LZTFL1) significantly reduces LZTFL1 expression in lung epithelial cell lines, demonstrating that this COVID-19 GWAS locus functionally regulates LZTFL1 transcription in airway cells.\",\n      \"method\": \"CRISPRi-mediated gene expression knockdown in lung epithelial cell lines, qRT-PCR\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPRi is a direct functional experiment; single lab, single method\",\n      \"pmids\": [\"34998241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through the ZNRF1-mediated ubiquitin proteasome pathway, inducing G1 cell cycle arrest; this was validated in kidney tumor cell lines and a patient-derived xenograft (PDX) model.\",\n      \"method\": \"LZTFL1 gain- and loss-of-function in ccRCC cell lines, Western blotting for AKT ubiquitination and stability, co-immunoprecipitation with ZNRF1, PDX lentiviral overexpression, flow cytometry cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional methods including PDX in vivo validation and Co-IP for ZNRF1 interaction, single lab\",\n      \"pmids\": [\"36966254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In LZTFL1-depleted mouse mesenchymal stem cells (CB-MSCs), Wnt/β-catenin signaling is inhibited: total β-catenin is reduced, LRP6 (Wnt co-receptor) is elevated at the cell surface and lipid rafts, and caveolin-1 (CAV1, required for LRP6-mediated Wnt activation) is reduced; this leads to increased nuclear glucocorticoid receptor and PPARγ, promoting enhanced adipogenesis.\",\n      \"method\": \"Lztfl1 knockout mouse, CB-MSC isolation and differentiation assay, Western blotting, flow cytometry, lipid raft fractionation, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO-derived primary cells with multiple pathway component analyses, single lab\",\n      \"pmids\": [\"39662832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of Lztfl1 in Neuro 2a neuronal cells promotes neurite outgrowth, indicating a role for LZTFL1 in neuronal differentiation.\",\n      \"method\": \"Lztfl1 overexpression in Neuro 2a cells, morphological analysis of neurite length\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single overexpression experiment, no mechanistic pathway identified, single lab\",\n      \"pmids\": [\"22093827\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LZTFL1 is a ciliary regulatory protein that acts as a negative regulator of BBSome ciliary trafficking by controlling BBS3-dependent BBSome loading at the basal body and IFT25/27-dependent BBSome reassembly at the ciliary tip, thereby governing Smoothened/Hedgehog signaling; in non-ciliary contexts it suppresses EMT by sequestering β-catenin in the cytoplasm, destabilizes AKT via the ZNRF1 ubiquitin-proteasome pathway, and regulates leptin receptor (LepRb)–STAT3 signaling in hypothalamic neurons to control energy homeostasis, while its expression is post-transcriptionally suppressed by miR-21 and the SNHG6–PTBP1 complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LZTFL1 is a cytoplasmic regulatory protein that governs ciliary trafficking of the BBSome and modulates epithelial-to-mesenchymal transition (EMT) signaling in multiple tissue contexts. It physically interacts with the BBSome complex and controls BBSome ciliary entry and exit by promoting BBS3 (ARL6) targeting to the basal body and stabilizing IFT25/27 for retrograde transport; loss of LZTFL1 disrupts Smoothened/Hedgehog signaling, photoreceptor outer segment integrity, and sperm flagella formation [PMID:22072986, PMID:34446551, PMID:27312011, PMID:34023333]. In non-ciliary contexts, LZTFL1 suppresses EMT by sequestering β-catenin in the cytoplasm to prevent its nuclear translocation, destabilizes AKT through ZNRF1-mediated ubiquitin-proteasome degradation to induce cell cycle arrest, and is required in hypothalamic neurons for leptin receptor–STAT3 signaling and energy homeostasis [PMID:25005785, PMID:36966254, PMID:30423168]. The COVID-19 risk allele rs17713054 upregulates LZTFL1 expression in lung epithelial cells via an enhancer element, linking increased LZTFL1 to EMT-associated pulmonary pathology [PMID:34737427, PMID:34998241].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that LZTFL1 is a physical interactor and negative regulator of BBSome ciliary trafficking resolved how the BBSome is restrained from constitutive ciliary entry and linked LZTFL1 to Hedgehog/Smoothened signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA epistasis, and fluorescence microscopy of ciliary localization in mammalian cell lines\",\n      \"pmids\": [\"22072986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which LZTFL1 physically restrains BBSome at the basal body not resolved\",\n        \"Whether LZTFL1 acts catalytically or as a stoichiometric scaffold unclear\",\n        \"In vivo consequence of LZTFL1–BBSome interaction not yet tested in animal models\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Patient fibroblasts with homozygous LZTFL1 deletion confirmed that LZTFL1 loss causes elevated ciliary Smoothened and activation of Hedgehog targets, establishing LZTFL1 as a disease-relevant negative regulator of Shh signaling in human cells.\",\n      \"evidence\": \"Immunofluorescence and protein expression analysis in patient-derived LZTFL1-null fibroblasts\",\n      \"pmids\": [\"22510444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Based on a single patient genotype; broader patient cohort not examined\",\n        \"Downstream transcriptional consequences (GLI target gene panel) not comprehensively profiled\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that LZTFL1 binds β-catenin cytoplasmically and prevents its nuclear translocation revealed a non-ciliary tumor-suppressive mechanism through EMT inhibition.\",\n      \"evidence\": \"Co-immunoprecipitation, proximity ligation assay, and Transwell migration/invasion assays in gastric cancer cells\",\n      \"pmids\": [\"25005785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether LZTFL1–β-catenin binding is direct or mediated by an adaptor not resolved\",\n        \"Structural basis of the interaction unknown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstration that LZTFL1 inhibits TGF-β–MAPK and Hedgehog signaling in lung epithelium and suppresses tumor colonization in vivo broadened its EMT-suppressive role beyond gastric to lung cancer.\",\n      \"evidence\": \"LZTFL1 knockdown/re-expression in NSCLC lines with pathway Western blots and mouse colonization assay\",\n      \"pmids\": [\"26364604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether LZTFL1 directly engages TGF-β receptor components or acts indirectly not determined\",\n        \"Single-lab in vivo colonization model\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Lztfl1 knockout mice revealed in vivo ciliary functions: LZTFL1 localizes to primary cilia, restrains BBS9 ciliary accumulation, and is essential for photoreceptor outer segment integrity, connecting BBSome regulation to retinal degeneration.\",\n      \"evidence\": \"Lztfl1 knockout mouse with immunofluorescence, electron microscopy, TUNEL assay, and subcellular fractionation in kidney and retina\",\n      \"pmids\": [\"27312011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism linking LZTFL1 loss to AP1 mislocalization in photoreceptors not elucidated\",\n        \"Whether photoreceptor degeneration is cell-autonomous not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional knockout studies showed LZTFL1 is required in hypothalamic neurons for leptin-stimulated STAT3 phosphorylation and energy homeostasis, establishing a brain-specific metabolic function independent of adipocyte LZTFL1.\",\n      \"evidence\": \"Conditional Lztfl1 knockout mouse with tissue-specific deletion, phospho-STAT3 immunoblotting, and leptin stimulation\",\n      \"pmids\": [\"30423168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular step at which LZTFL1 enables LepRb–STAT3 coupling not identified\",\n        \"Whether the metabolic phenotype is cilium-dependent or cilium-independent not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of miR-21 as a direct post-transcriptional repressor of LZTFL1 defined an upstream regulatory axis (miR-21→LZTFL1→EMT) in breast cancer.\",\n      \"evidence\": \"Luciferase 3′ UTR reporter assay, epistasis by co-transfection, in vivo mouse tumor model\",\n      \"pmids\": [\"31351450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether other miRNAs redundantly target LZTFL1 not explored\",\n        \"Tissue specificity of miR-21 regulation of LZTFL1 not addressed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistic dissection in Chlamydomonas resolved LZTFL1's dual control over BBSome dynamics: promoting BBS3-dependent anterograde loading at the basal body and stabilizing IFT25/27 for retrograde reassembly at the ciliary tip.\",\n      \"evidence\": \"Chlamydomonas LZTFL1 mutant with BBSome/IFT fluorescence microscopy, genetic rescue, and phototaxis behavioral assay\",\n      \"pmids\": [\"34446551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the dual-control model fully applies in mammalian cilia not confirmed\",\n        \"Biochemical basis of LZTFL1-dependent IFT25/27 stabilization unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"LZTFL1 was shown to selectively stabilize IFT27 during spermatogenesis; its loss causes asthenoteratozoospermia and male infertility, extending the IFT-stabilization mechanism to mammalian motile cilia/flagella.\",\n      \"evidence\": \"Lztfl1 knockout mouse sperm analysis, IFT protein Western blots, in vitro fertilization assay\",\n      \"pmids\": [\"34023333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether IFT27 instability is the sole cause of flagellar defects not determined\",\n        \"Rescue by IFT27 re-expression not performed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The COVID-19 risk allele rs17713054 was functionally linked to LZTFL1 upregulation in lung epithelium through an enhancer, connecting LZTFL1 expression levels to severe COVID-19 via EMT-related pathways.\",\n      \"evidence\": \"Chromosome conformation capture, gene expression analysis, and spatial transcriptomics of COVID-19 lung biopsies\",\n      \"pmids\": [\"34737427\", \"34998241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether LZTFL1 overexpression directly impairs antiviral defense or acts through EMT-related barrier disruption not resolved\",\n        \"Causal rescue experiments (LZTFL1 normalization in risk-allele cells) not reported\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that LZTFL1 destabilizes AKT through ZNRF1-mediated ubiquitination defined a non-ciliary tumor-suppressive mechanism distinct from β-catenin sequestration, causing G1 arrest in kidney cancer.\",\n      \"evidence\": \"LZTFL1 gain/loss-of-function in ccRCC cell lines, Co-IP with ZNRF1, AKT ubiquitination assays, PDX model\",\n      \"pmids\": [\"36966254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether LZTFL1 acts as a scaffold bridging ZNRF1 to AKT or has a separate role not resolved\",\n        \"Generalizability beyond ccRCC not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"In Lztfl1 KO mesenchymal stem cells, Wnt/β-catenin signaling is paradoxically inhibited—with reduced total β-catenin and caveolin-1—leading to enhanced adipogenesis, revealing a context-dependent role for LZTFL1 in Wnt pathway modulation.\",\n      \"evidence\": \"Lztfl1 knockout mouse CB-MSC differentiation assays, lipid raft fractionation, Western blotting, flow cytometry\",\n      \"pmids\": [\"39662832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Apparent contradiction with gastric cancer data (where LZTFL1 loss activates β-catenin) not mechanistically reconciled\",\n        \"Whether caveolin-1 reduction is a direct or indirect consequence of LZTFL1 loss unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of LZTFL1's interaction with the BBSome and β-catenin, whether its ciliary and non-ciliary functions are mechanistically separable, and how tissue context determines whether LZTFL1 loss activates or inhibits Wnt/β-catenin signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of LZTFL1 or its complexes available\",\n        \"Separation-of-function mutants distinguishing ciliary from EMT roles not generated\",\n        \"Reconciliation of opposing β-catenin outcomes in different cell types not achieved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6, 14]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 5, 8, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"complexes\": [\n      \"BBSome\"\n    ],\n    \"partners\": [\n      \"BBS3\",\n      \"BBS5\",\n      \"BBS9\",\n      \"IFT27\",\n      \"CTNNB1\",\n      \"ZNRF1\",\n      \"PTBP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}