{"gene":"LZTFL1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2011,"finding":"LZTFL1 physically interacts with the BBSome complex and negatively regulates BBSome ciliary trafficking; knockdown of LZTFL1 restores BBSome trafficking to cilia in BBS3- and BBS5-depleted cells, placing LZTFL1 as a negative regulator upstream of BBSome ciliary entry. All BBSome subunits and BBS3 (ARL6) are required for BBSome ciliary entry.","method":"Co-immunoprecipitation, siRNA knockdown, fluorescence microscopy/ciliary localization assays, genetic epistasis (double knockdown rescue)","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, epistasis by double knockdown, multiple orthogonal methods in a focused mechanistic study","pmids":["22072986"],"is_preprint":false},{"year":2011,"finding":"LZTFL1 and BBS proteins regulate ciliary trafficking of the Hedgehog signal transducer Smoothened; depletion of LZTFL1 alters Smoothened ciliary localization.","method":"siRNA knockdown, fluorescence microscopy of Smoothened ciliary localization","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined ciliary localization readout, single lab, single study","pmids":["22072986"],"is_preprint":false},{"year":2012,"finding":"Loss of LZTFL1 in patient fibroblasts (homozygous 5 bp deletion) causes massive activation of the Sonic Hedgehog (Shh) pathway, including significant upregulation of Smoothened, Patched1, and the downstream target GLI2, confirming LZTFL1 as a negative regulator of Shh signaling in human cells.","method":"Patient fibroblast analysis (Western blot, RT-PCR), loss-of-function due to frameshift mutation","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human loss-of-function validated in patient cells with multiple pathway readouts, 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-associated gene expression, 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, overexpression and knockdown","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus orthogonal proximity ligation assay confirming cytoplasmic interaction, single lab","pmids":["25005785"],"is_preprint":false},{"year":2015,"finding":"LZTFL1 inhibits TGF-β-activated MAPK and Hedgehog signaling in lung bronchial epithelial cells, and its expression correlates with ciliated cell differentiation; re-expression suppresses EMT marker changes, extravasation, and tumor colonization in vivo.","method":"Western blot (pathway readouts), re-expression in tumor cell lines, in vivo colonization assay in mice, loss-of-function","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling pathway readouts with in vivo validation, single lab","pmids":["26364604"],"is_preprint":false},{"year":2015,"finding":"LZTFL1 accumulates at the plasma membrane in CD4+ T cells and transiently redistributes to the immunological synapse contact zone upon T cell–APC interaction, then relocates to the distal pole; knockdown reduces IL-5 production and overexpression enhances TCR-mediated NFAT signaling.","method":"Live-cell imaging, siRNA knockdown, overexpression, NFAT luciferase reporter, cytokine ELISA","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging of subcellular redistribution with functional consequence (IL-5, NFAT), single lab, multiple methods","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, shortens photoreceptor outer segments, enlarges the distal axoneme of the photoreceptor connecting cilium, causes rhodopsin mislocalization to the outer nuclear layer, and increases AP1 adaptor complex in photoreceptors, leading to photoreceptor apoptosis.","method":"Knockout mouse model, immunofluorescence/subcellular fractionation, TUNEL assay, electron microscopy","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple defined cellular and ultrastructural phenotypic readouts, single lab","pmids":["27312011"],"is_preprint":false},{"year":2018,"finding":"Global Lztfl1 knockout causes hyperphagia and leptin resistance; Lztfl1 deficiency in brain (but not adipocytes) is responsible for the obese phenotype; LZTFL1 loss abolishes leptin-stimulated STAT3 phosphorylation in the hypothalamic LepRb signaling pathway without affecting LepRb membrane localization; Lztfl1-/- MEFs have significantly longer primary cilia; Lztfl1 interacts with proteins involved in actin/cytoskeleton dynamics.","method":"Conditional/global knockout mice, leptin stimulation + STAT3 phosphorylation assay (Western blot), tissue-specific rescue, live-cell cilia measurement, Co-immunoprecipitation","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with pathway epistasis (STAT3), tissue-specific knockout to place gene in brain, single lab","pmids":["30423168"],"is_preprint":false},{"year":2021,"finding":"LZTFL1 maintains BBSome dynamics in Chlamydomonas cilia via a dual mechanism: (1) it promotes BBS3 (ARL6 GTPase) targeting to the basal body, thereby directing BBSome recruitment to basal body and loading onto anterograde IFT trains; (2) it stabilizes the IFT25/27 subcomplex in the cell body, which in turn promotes BBSome reassembly at the ciliary tip for loading onto retrograde IFT trains. Loss of LZTFL1 depletes BBSome from cilia and causes phototaxis defects.","method":"Chlamydomonas reinhardtii genetics, fluorescence microscopy, IFT assay, co-immunoprecipitation, epistasis by combinatorial mutant analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, Co-IP, genetic epistasis) in an ortholog, dual mechanism established with mutant rescue","pmids":["34446551"],"is_preprint":false},{"year":2021,"finding":"LZTFL1 is required for normal sperm flagella structure and motility; LZTFL1 knockout mice show reduced male fertility, asthenoteratozoospermia, and reduced fertilization. Absence of LZTFL1 specifically decreases testicular IFT27 protein levels while other IFT proteins (IFT20, IFT81, IFT88, IFT140) remain stable, indicating LZTFL1 is required to stabilize IFT27 in vivo. LZTFL1 is expressed in developing flagella and near the manchette of elongated spermatids.","method":"Knockout mouse model, Western blot (IFT protein levels), immunofluorescence localization, sperm motility analysis, in vitro fertilization assay","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple phenotypic readouts and specific IFT27 destabilization as molecular mechanism, single lab","pmids":["34023333"],"is_preprint":false},{"year":2021,"finding":"LZTFL1 mRNA is upregulated by the rs17713054 risk allele enhancer at the 3p21.31 COVID-19 locus, as shown by chromosome conformation capture; LZTFL1 upregulation is associated with EMT activation in lung epithelial cells of COVID-19 patients, identified by spatial transcriptomics of biopsies.","method":"Chromosome conformation capture (3C/Hi-C), gene expression analysis, spatial transcriptomics of patient biopsies, multiomics + machine learning","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromosome conformation capture linking enhancer to LZTFL1, orthogonal spatial transcriptomics in patient tissue, single study","pmids":["34737427"],"is_preprint":false},{"year":2022,"finding":"CRISPRi targeting a region near rs11385942 in the intron 5 of LZTFL1 significantly reduces LZTFL1 expression in lung epithelial cell lines, functionally confirming that the COVID-19 GWAS locus regulates LZTFL1 transcription.","method":"CRISPRi-mediated gene expression knockdown in lung epithelial cell lines, qRT-PCR","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPRi functional validation of regulatory locus effect on LZTFL1, single lab","pmids":["34998241"],"is_preprint":false},{"year":2021,"finding":"SNHG6 lncRNA promotes LZTFL1 mRNA destabilization by facilitating PTBP1 binding to LZTFL1 mRNA; the SNHG6-PTBP1 complex degrades LZTFL1 mRNA in hepatoma cells, reducing LZTFL1 protein levels.","method":"Quantitative proteomics (identifying PTBP1 as SNHG6-interacting protein), RNA immunoprecipitation, mRNA stability assay, knockdown/overexpression","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus RNA-IP identifying post-transcriptional mechanism, single lab","pmids":["34252487"],"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.","method":"Gain- and loss-of-function studies in kidney tumor cell lines, patient-derived xenograft (PDX) model with lentiviral LZTFL1 re-expression, Western blot for AKT levels, cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue in PDX plus cell-line loss/gain-of-function with defined AKT/ZNRF1 pathway mechanism, single lab","pmids":["36966254"],"is_preprint":false},{"year":2024,"finding":"In Lztfl1 knockout mesenchymal stem cells (CB-MSCs), canonical Wnt/β-catenin signaling is suppressed (reduced total β-catenin), while adipogenesis-favoring factors (PPARγ, nuclear glucocorticoid receptor) are elevated; elevated LRP6 and reduced caveolin-1 (CAV1) at lipid rafts indicate impaired Wnt pathway activation, leading to enhanced adipogenesis.","method":"Knockout mouse MSC isolation, Western blot, flow cytometry, lipid-raft fractionation, cell-surface LRP6 assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple biochemical readouts across Wnt pathway components, single lab","pmids":["39662832"],"is_preprint":false},{"year":2024,"finding":"LZTFL1 knockdown in an OVA-induced asthma mouse model attenuates Th2-type inflammation; LZTFL1 knockdown inhibits MEK/ERK signaling and reduces GATA3 protein levels (without affecting GATA3 mRNA stability), and reduces GATA3+CD4+ Th2 cell numbers, suggesting LZTFL1 acts via the ERK/GATA3 axis to regulate Th2 differentiation.","method":"Lentiviral shRNA knockdown in OVA mouse model, Western blot, flow cytometry, cytokine ELISA, mRNA stability assay","journal":"Molecular immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo knockdown with pathway readouts but mechanism inferred indirectly (ERK→GATA3 protein stabilization not directly demonstrated), single lab","pmids":["38310669"],"is_preprint":false},{"year":2011,"finding":"Overexpression of Lztfl1 in Neuro 2a cells promotes neurite outgrowth, suggesting a functional role in neuronal process extension.","method":"Overexpression in Neuro 2a cells, morphological neurite measurement","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression assay, single lab, no mechanism established","pmids":["22093827"],"is_preprint":false}],"current_model":"LZTFL1 is a ciliary trafficking regulator that acts as a negative regulator of the BBSome complex by controlling BBSome recruitment to the basal body (via BBS3/ARL6) and BBSome reassembly at the ciliary tip (via IFT25/27 stabilization), thereby governing Smoothened/Hedgehog ciliary signaling; it also suppresses EMT by binding and retaining β-catenin in the cytoplasm, destabilizes AKT via the ZNRF1 ubiquitin-proteasome pathway, modulates leptin receptor (LepRb)/STAT3 signaling in hypothalamic neurons, and participates in T cell activation at the immunological synapse — with loss-of-function causing the ciliopathy Bardet-Biedl syndrome (BBS17) and gain-of-function at the 3p21.31 locus associated with severe COVID-19 through EMT activation in lung epithelial cells."},"narrative":{"mechanistic_narrative":"LZTFL1 is a cytoplasmic and ciliary trafficking regulator that governs the dynamics of the BBSome complex during ciliogenesis [PMID:22072986, PMID:34446551]. It physically associates with the BBSome and acts as a negative regulator of BBSome ciliary entry, since LZTFL1 depletion restores BBSome trafficking in cells lacking BBS3 (ARL6) or BBS5 [PMID:22072986]. Mechanistically, LZTFL1 maintains BBSome dynamics through a dual mechanism: it promotes BBS3/ARL6 targeting to the basal body to direct BBSome loading onto anterograde IFT trains, and it stabilizes the IFT25/27 subcomplex to enable BBSome reassembly at the ciliary tip for retrograde transport [PMID:34446551], with the requirement for IFT27 stabilization confirmed in vivo [PMID:34023333]. Through this control of ciliary trafficking, LZTFL1 negatively regulates Hedgehog signaling, restraining ciliary Smoothened, Patched1, and GLI2 such that its loss in patient cells produces massive Shh pathway activation [PMID:22072986, PMID:22510444]. Loss of LZTFL1 disrupts ciliary architecture and protein sorting in photoreceptors, causing rhodopsin mislocalization and photoreceptor apoptosis [PMID:27312011], and is required for normal sperm flagellar structure and male fertility [PMID:34023333]. Beyond cilia, LZTFL1 binds β-catenin in the cytoplasm to block its nuclear translocation and suppress EMT, migration, and invasion [PMID:25005785], inhibits TGF-β-activated MAPK and Hedgehog signaling in lung epithelial cells [PMID:26364604], destabilizes AKT via the ZNRF1 ubiquitin-proteasome pathway to enforce G1 arrest in kidney tumor cells [PMID:36966254], and modulates hypothalamic leptin receptor/STAT3 signaling, with knockout mice showing hyperphagia and leptin resistance [PMID:30423168]. At the immunological synapse, LZTFL1 redistributes upon T cell–APC engagement and modulates TCR/NFAT signaling and cytokine output [PMID:26700766]. LZTFL1 expression is controlled post-transcriptionally and by enhancers at the 3p21.31 locus, where a risk allele upregulates LZTFL1 in association with EMT activation in lung epithelium of severe COVID-19 patients [PMID:34737427, PMID:34998241].","teleology":[{"year":2011,"claim":"Established LZTFL1 as a direct physical partner and negative regulator of the BBSome, answering where it sits relative to BBSome ciliary entry and linking it to Hedgehog signal transduction.","evidence":"Reciprocal Co-IP, siRNA knockdown with double-knockdown epistasis, and ciliary localization imaging of Smoothened in mammalian cells","pmids":["22072986"],"confidence":"High","gaps":["Did not resolve the molecular step at which LZTFL1 blocks BBSome entry","Smoothened readout was correlative localization rather than direct binding"]},{"year":2012,"claim":"Confirmed in human loss-of-function cells that LZTFL1 is a negative regulator of Shh signaling, validating the ciliopathy-relevant pathway consequence of its loss.","evidence":"Western blot and RT-PCR of Smoothened, Patched1, and GLI2 in patient fibroblasts carrying a frameshift deletion","pmids":["22510444"],"confidence":"Medium","gaps":["Single patient genotype","Did not distinguish direct ciliary trafficking effects from secondary transcriptional changes"]},{"year":2014,"claim":"Defined a cilium-independent role: LZTFL1 sequesters β-catenin in the cytoplasm to suppress EMT, broadening its function into Wnt-associated tumor suppression.","evidence":"Reciprocal Co-IP, in situ proximity ligation, and migration/invasion/zymography assays in gastric cancer cells","pmids":["25005785"],"confidence":"Medium","gaps":["Binding interface on β-catenin not mapped","Single cancer cell context"]},{"year":2015,"claim":"Extended the EMT-suppressive role to lung epithelium and demonstrated in vivo tumor suppression, tying LZTFL1 to ciliated-cell differentiation and TGF-β/MAPK/Hedgehog signaling.","evidence":"Re-expression in tumor lines, pathway Western blots, and in vivo colonization assays in mice","pmids":["26364604"],"confidence":"Medium","gaps":["Multiple pathways implicated without defining the primary direct target","Single lab"]},{"year":2015,"claim":"Identified a role in immune cells, showing LZTFL1 redistributes to the immunological synapse and tunes TCR-mediated NFAT signaling and cytokine output.","evidence":"Live-cell imaging, knockdown/overexpression, NFAT luciferase reporter, and cytokine ELISA in CD4+ T cells","pmids":["26700766"],"confidence":"Medium","gaps":["Molecular partners at the synapse not identified","Connection to ciliary trafficking machinery unclear"]},{"year":2016,"claim":"Defined the in vivo ciliary phenotype of LZTFL1 loss, showing it regulates BBSome ciliary content and is required for photoreceptor outer segment integrity and protein sorting.","evidence":"Lztfl1 knockout mice with immunofluorescence, fractionation, TUNEL, and electron microscopy of photoreceptors","pmids":["27312011"],"confidence":"Medium","gaps":["Mechanism linking AP1 adaptor increase to rhodopsin mislocalization not resolved","Single model organism readout"]},{"year":2018,"claim":"Placed LZTFL1 in hypothalamic leptin signaling, showing its loss abolishes leptin-stimulated STAT3 phosphorylation and drives obesity through a brain-specific requirement.","evidence":"Global and tissue-specific knockout mice, leptin-stimulated STAT3 phosphorylation Western blots, cilia measurement, and Co-IP","pmids":["30423168"],"confidence":"Medium","gaps":["Step at which LZTFL1 couples LepRb to STAT3 not defined","Actin/cytoskeleton interactors not individually validated"]},{"year":2021,"claim":"Resolved the dual molecular mechanism of LZTFL1 in BBSome dynamics — basal-body recruitment via BBS3/ARL6 and tip reassembly via IFT25/27 stabilization — using a tractable ciliary genetic system.","evidence":"Chlamydomonas genetics, IFT imaging assays, Co-IP, and combinatorial mutant epistasis","pmids":["34446551"],"confidence":"High","gaps":["Conservation of the exact dual mechanism in mammalian cilia not fully demonstrated","Structural basis of BBS3 and IFT25/27 binding unresolved"]},{"year":2021,"claim":"Confirmed in vivo that LZTFL1 specifically stabilizes IFT27, linking its trafficking function to flagellar assembly and male fertility.","evidence":"Knockout mouse with selective loss of testicular IFT27, sperm motility analysis, and in vitro fertilization","pmids":["34023333"],"confidence":"Medium","gaps":["Direct LZTFL1–IFT27 binding interface not mapped","Whether stabilization is via direct binding or pathway effect unresolved"]},{"year":2021,"claim":"Identified how the 3p21.31 COVID-19 risk locus acts, showing the risk allele enhancer upregulates LZTFL1 in association with EMT activation in patient lung epithelium.","evidence":"Chromosome conformation capture, expression analysis, and spatial transcriptomics of patient biopsies with machine learning","pmids":["34737427"],"confidence":"Medium","gaps":["Causal chain from LZTFL1 upregulation to disease severity not experimentally dissected","EMT association is correlative in tissue"]},{"year":2021,"claim":"Defined a post-transcriptional control mechanism, showing the SNHG6 lncRNA recruits PTBP1 to destabilize LZTFL1 mRNA in hepatoma cells.","evidence":"Quantitative proteomics, RNA immunoprecipitation, and mRNA stability assays","pmids":["34252487"],"confidence":"Medium","gaps":["Functional consequence of LZTFL1 loss in this context not fully traced","Single cancer model"]},{"year":2022,"claim":"Functionally confirmed that the COVID-19 GWAS locus regulates LZTFL1 transcription, validating LZTFL1 as the causal gene at the locus.","evidence":"CRISPRi targeting near rs11385942 in intron 5 with qRT-PCR in lung epithelial cell lines","pmids":["34998241"],"confidence":"Medium","gaps":["Downstream phenotypic effect of reduced LZTFL1 not measured here","Single cell-line context"]},{"year":2023,"claim":"Defined a proliferation-control mechanism, showing LZTFL1 destabilizes AKT through the ZNRF1 ubiquitin-proteasome pathway to enforce G1 arrest.","evidence":"Gain/loss-of-function in kidney tumor lines, PDX rescue, AKT Western blots, and cell cycle analysis","pmids":["36966254"],"confidence":"Medium","gaps":["Direct LZTFL1–ZNRF1 interaction not structurally characterized","Single tumor type"]},{"year":2024,"claim":"Linked LZTFL1 to canonical Wnt/β-catenin signaling and adipogenesis, showing its loss in MSCs suppresses Wnt activation and favors fat differentiation.","evidence":"Knockout MSCs analyzed by Western blot, flow cytometry, lipid-raft fractionation, and cell-surface LRP6 assay","pmids":["39662832"],"confidence":"Medium","gaps":["Mechanism connecting LZTFL1 to CAV1/LRP6 raft organization unresolved","Single cell system"]},{"year":2024,"claim":"Implicated LZTFL1 in Th2 differentiation via an ERK/GATA3 axis in allergic airway inflammation.","evidence":"Lentiviral shRNA knockdown in an OVA asthma mouse model with Western blot, flow cytometry, and cytokine ELISA","pmids":["38310669"],"confidence":"Low","gaps":["ERK→GATA3 protein stabilization not directly demonstrated","Mechanism inferred indirectly","Single lab"]},{"year":null,"claim":"How LZTFL1's conserved ciliary trafficking function mechanistically connects to its many non-ciliary roles (β-catenin, AKT/ZNRF1, leptin/STAT3, ERK/GATA3) remains unresolved, as does the structural basis of its interactions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of LZTFL1 with BBSome, BBS3, or IFT25/27","Whether cytoplasmic signaling roles are separable from ciliary trafficking unknown","No unifying biochemical activity defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[6,8]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,8]}],"complexes":["BBSome"],"partners":["BBS3","ARL6","IFT27","IFT25","CTNNB1","ZNRF1","PTBP1"],"other_free_text":[]}},"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":214,"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":166,"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":114,"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":"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":"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":"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":"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":28,"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":"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":"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":18,"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":"34023333","id":"PMC_34023333","title":"Leucine zipper transcription factor-like 1 (LZTFL1), an intraflagellar transporter protein 27 (IFT27) associated protein, is required for normal sperm function and male fertility.","date":"2021","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34023333","citation_count":13,"is_preprint":false},{"pmid":"22093827","id":"PMC_22093827","title":"Involvement of leucine zipper transcription factor-like protein 1 (Lztfl1) in the attenuation of cognitive impairment by exercise training.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22093827","citation_count":9,"is_preprint":false},{"pmid":"39662832","id":"PMC_39662832","title":"Aberrant Wnt/β-catenin signaling in the mesenchymal stem cells of LZTFL1-depleted mice leads to increased adipogenesis, with implications for obesity.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39662832","citation_count":6,"is_preprint":false},{"pmid":"37795896","id":"PMC_37795896","title":"ABCA3 and 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 pathway.","date":"2024","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38310669","citation_count":4,"is_preprint":false},{"pmid":"31371991","id":"PMC_31371991","title":"Tumor suppressive functions of LZTFL1 in hepatocellular carcinoma.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31371991","citation_count":3,"is_preprint":false},{"pmid":"38801250","id":"PMC_38801250","title":"LZTFL1, a rare cause of Bardet-Biedl syndrome: A new patient with severe short stature and moderate intellectual disability, more than casual associations?","date":"2024","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/38801250","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.01.679818","title":"Neanderthal Introgressed COVID-19 Risk Locus 3p21.31 Under Positive Selection in East Asia via LZTFL1-Driven Ciliary Changes","date":"2025-10-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.01.679818","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.01.25330014","title":"Immune Cell-Based Transcriptomic Mendelian Randomization and Colocalization Study on Type 1 Diabetes","date":"2025-07-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.01.25330014","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15841,"output_tokens":4198,"usd":0.055246,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12208,"output_tokens":4776,"usd":0.09022,"stage2_stop_reason":"end_turn"},"total_usd":0.145466,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"LZTFL1 physically interacts with the BBSome complex and negatively regulates BBSome ciliary trafficking; knockdown of LZTFL1 restores BBSome trafficking to cilia in BBS3- and BBS5-depleted cells, placing LZTFL1 as a negative regulator upstream of BBSome ciliary entry. All BBSome subunits and BBS3 (ARL6) are required for BBSome ciliary entry.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, fluorescence microscopy/ciliary localization assays, genetic epistasis (double knockdown rescue)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, epistasis by double knockdown, multiple orthogonal methods in a focused mechanistic study\",\n      \"pmids\": [\"22072986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LZTFL1 and BBS proteins regulate ciliary trafficking of the Hedgehog signal transducer Smoothened; depletion of LZTFL1 alters Smoothened ciliary localization.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy of Smoothened ciliary localization\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined ciliary localization readout, single lab, single study\",\n      \"pmids\": [\"22072986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of LZTFL1 in patient fibroblasts (homozygous 5 bp deletion) causes massive activation of the Sonic Hedgehog (Shh) pathway, including significant upregulation of Smoothened, Patched1, and the downstream target GLI2, confirming LZTFL1 as a negative regulator of Shh signaling in human cells.\",\n      \"method\": \"Patient fibroblast analysis (Western blot, RT-PCR), loss-of-function due to frameshift mutation\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human loss-of-function validated in patient cells with multiple pathway readouts, 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-associated gene expression, 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, overexpression and knockdown\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus orthogonal proximity ligation assay confirming cytoplasmic interaction, single lab\",\n      \"pmids\": [\"25005785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LZTFL1 inhibits TGF-β-activated MAPK and Hedgehog signaling in lung bronchial epithelial cells, and its expression correlates with ciliated cell differentiation; re-expression suppresses EMT marker changes, extravasation, and tumor colonization in vivo.\",\n      \"method\": \"Western blot (pathway readouts), re-expression in tumor cell lines, in vivo colonization assay in mice, loss-of-function\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling pathway readouts with 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 in CD4+ T cells and transiently redistributes to the immunological synapse contact zone upon T cell–APC interaction, then relocates to the distal pole; knockdown reduces IL-5 production and overexpression enhances TCR-mediated NFAT signaling.\",\n      \"method\": \"Live-cell imaging, siRNA knockdown, overexpression, NFAT luciferase reporter, cytokine ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging of subcellular redistribution with functional consequence (IL-5, NFAT), single lab, multiple methods\",\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, shortens photoreceptor outer segments, enlarges the distal axoneme of the photoreceptor connecting cilium, causes rhodopsin mislocalization to the outer nuclear layer, and increases AP1 adaptor complex in photoreceptors, leading to photoreceptor apoptosis.\",\n      \"method\": \"Knockout mouse model, immunofluorescence/subcellular fractionation, TUNEL assay, electron microscopy\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple defined cellular and ultrastructural phenotypic readouts, single lab\",\n      \"pmids\": [\"27312011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Global Lztfl1 knockout causes hyperphagia and leptin resistance; Lztfl1 deficiency in brain (but not adipocytes) is responsible for the obese phenotype; LZTFL1 loss abolishes leptin-stimulated STAT3 phosphorylation in the hypothalamic LepRb signaling pathway without affecting LepRb membrane localization; Lztfl1-/- MEFs have significantly longer primary cilia; Lztfl1 interacts with proteins involved in actin/cytoskeleton dynamics.\",\n      \"method\": \"Conditional/global knockout mice, leptin stimulation + STAT3 phosphorylation assay (Western blot), tissue-specific rescue, live-cell cilia measurement, Co-immunoprecipitation\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with pathway epistasis (STAT3), tissue-specific knockout to place gene in brain, single lab\",\n      \"pmids\": [\"30423168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LZTFL1 maintains BBSome dynamics in Chlamydomonas cilia via a dual mechanism: (1) it promotes BBS3 (ARL6 GTPase) targeting to the basal body, thereby directing BBSome recruitment to basal body and loading onto anterograde IFT trains; (2) it stabilizes the IFT25/27 subcomplex in the cell body, which in turn promotes BBSome reassembly at the ciliary tip for loading onto retrograde IFT trains. Loss of LZTFL1 depletes BBSome from cilia and causes phototaxis defects.\",\n      \"method\": \"Chlamydomonas reinhardtii genetics, fluorescence microscopy, IFT assay, co-immunoprecipitation, epistasis by combinatorial mutant analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, Co-IP, genetic epistasis) in an ortholog, dual mechanism established with mutant rescue\",\n      \"pmids\": [\"34446551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LZTFL1 is required for normal sperm flagella structure and motility; LZTFL1 knockout mice show reduced male fertility, asthenoteratozoospermia, and reduced fertilization. Absence of LZTFL1 specifically decreases testicular IFT27 protein levels while other IFT proteins (IFT20, IFT81, IFT88, IFT140) remain stable, indicating LZTFL1 is required to stabilize IFT27 in vivo. LZTFL1 is expressed in developing flagella and near the manchette of elongated spermatids.\",\n      \"method\": \"Knockout mouse model, Western blot (IFT protein levels), immunofluorescence localization, sperm motility analysis, in vitro fertilization assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple phenotypic readouts and specific IFT27 destabilization as molecular mechanism, single lab\",\n      \"pmids\": [\"34023333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LZTFL1 mRNA is upregulated by the rs17713054 risk allele enhancer at the 3p21.31 COVID-19 locus, as shown by chromosome conformation capture; LZTFL1 upregulation is associated with EMT activation in lung epithelial cells of COVID-19 patients, identified by spatial transcriptomics of biopsies.\",\n      \"method\": \"Chromosome conformation capture (3C/Hi-C), gene expression analysis, spatial transcriptomics of patient biopsies, multiomics + machine learning\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromosome conformation capture linking enhancer to LZTFL1, orthogonal spatial transcriptomics in patient tissue, single study\",\n      \"pmids\": [\"34737427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPRi targeting a region near rs11385942 in the intron 5 of LZTFL1 significantly reduces LZTFL1 expression in lung epithelial cell lines, functionally confirming that the COVID-19 GWAS locus regulates LZTFL1 transcription.\",\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 / Moderate — CRISPRi functional validation of regulatory locus effect on LZTFL1, single lab\",\n      \"pmids\": [\"34998241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNHG6 lncRNA promotes LZTFL1 mRNA destabilization by facilitating PTBP1 binding to LZTFL1 mRNA; the SNHG6-PTBP1 complex degrades LZTFL1 mRNA in hepatoma cells, reducing LZTFL1 protein levels.\",\n      \"method\": \"Quantitative proteomics (identifying PTBP1 as SNHG6-interacting protein), RNA immunoprecipitation, mRNA stability assay, knockdown/overexpression\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus RNA-IP identifying post-transcriptional mechanism, single lab\",\n      \"pmids\": [\"34252487\"],\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.\",\n      \"method\": \"Gain- and loss-of-function studies in kidney tumor cell lines, patient-derived xenograft (PDX) model with lentiviral LZTFL1 re-expression, Western blot for AKT levels, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue in PDX plus cell-line loss/gain-of-function with defined AKT/ZNRF1 pathway mechanism, single lab\",\n      \"pmids\": [\"36966254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Lztfl1 knockout mesenchymal stem cells (CB-MSCs), canonical Wnt/β-catenin signaling is suppressed (reduced total β-catenin), while adipogenesis-favoring factors (PPARγ, nuclear glucocorticoid receptor) are elevated; elevated LRP6 and reduced caveolin-1 (CAV1) at lipid rafts indicate impaired Wnt pathway activation, leading to enhanced adipogenesis.\",\n      \"method\": \"Knockout mouse MSC isolation, Western blot, flow cytometry, lipid-raft fractionation, cell-surface LRP6 assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple biochemical readouts across Wnt pathway components, single lab\",\n      \"pmids\": [\"39662832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LZTFL1 knockdown in an OVA-induced asthma mouse model attenuates Th2-type inflammation; LZTFL1 knockdown inhibits MEK/ERK signaling and reduces GATA3 protein levels (without affecting GATA3 mRNA stability), and reduces GATA3+CD4+ Th2 cell numbers, suggesting LZTFL1 acts via the ERK/GATA3 axis to regulate Th2 differentiation.\",\n      \"method\": \"Lentiviral shRNA knockdown in OVA mouse model, Western blot, flow cytometry, cytokine ELISA, mRNA stability assay\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo knockdown with pathway readouts but mechanism inferred indirectly (ERK→GATA3 protein stabilization not directly demonstrated), single lab\",\n      \"pmids\": [\"38310669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of Lztfl1 in Neuro 2a cells promotes neurite outgrowth, suggesting a functional role in neuronal process extension.\",\n      \"method\": \"Overexpression in Neuro 2a cells, morphological neurite measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression assay, single lab, no mechanism established\",\n      \"pmids\": [\"22093827\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LZTFL1 is a ciliary trafficking regulator that acts as a negative regulator of the BBSome complex by controlling BBSome recruitment to the basal body (via BBS3/ARL6) and BBSome reassembly at the ciliary tip (via IFT25/27 stabilization), thereby governing Smoothened/Hedgehog ciliary signaling; it also suppresses EMT by binding and retaining β-catenin in the cytoplasm, destabilizes AKT via the ZNRF1 ubiquitin-proteasome pathway, modulates leptin receptor (LepRb)/STAT3 signaling in hypothalamic neurons, and participates in T cell activation at the immunological synapse — with loss-of-function causing the ciliopathy Bardet-Biedl syndrome (BBS17) and gain-of-function at the 3p21.31 locus associated with severe COVID-19 through EMT activation in lung epithelial cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LZTFL1 is a cytoplasmic and ciliary trafficking regulator that governs the dynamics of the BBSome complex during ciliogenesis [#0, #8]. It physically associates with the BBSome and acts as a negative regulator of BBSome ciliary entry, since LZTFL1 depletion restores BBSome trafficking in cells lacking BBS3 (ARL6) or BBS5 [#0]. Mechanistically, LZTFL1 maintains BBSome dynamics through a dual mechanism: it promotes BBS3/ARL6 targeting to the basal body to direct BBSome loading onto anterograde IFT trains, and it stabilizes the IFT25/27 subcomplex to enable BBSome reassembly at the ciliary tip for retrograde transport [#8], with the requirement for IFT27 stabilization confirmed in vivo [#9]. Through this control of ciliary trafficking, LZTFL1 negatively regulates Hedgehog signaling, restraining ciliary Smoothened, Patched1, and GLI2 such that its loss in patient cells produces massive Shh pathway activation [#1, #2]. Loss of LZTFL1 disrupts ciliary architecture and protein sorting in photoreceptors, causing rhodopsin mislocalization and photoreceptor apoptosis [#6], and is required for normal sperm flagellar structure and male fertility [#9]. Beyond cilia, LZTFL1 binds β-catenin in the cytoplasm to block its nuclear translocation and suppress EMT, migration, and invasion [#3], inhibits TGF-β-activated MAPK and Hedgehog signaling in lung epithelial cells [#4], destabilizes AKT via the ZNRF1 ubiquitin-proteasome pathway to enforce G1 arrest in kidney tumor cells [#13], and modulates hypothalamic leptin receptor/STAT3 signaling, with knockout mice showing hyperphagia and leptin resistance [#7]. At the immunological synapse, LZTFL1 redistributes upon T cell–APC engagement and modulates TCR/NFAT signaling and cytokine output [#5]. LZTFL1 expression is controlled post-transcriptionally and by enhancers at the 3p21.31 locus, where a risk allele upregulates LZTFL1 in association with EMT activation in lung epithelium of severe COVID-19 patients [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established LZTFL1 as a direct physical partner and negative regulator of the BBSome, answering where it sits relative to BBSome ciliary entry and linking it to Hedgehog signal transduction.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown with double-knockdown epistasis, and ciliary localization imaging of Smoothened in mammalian cells\",\n      \"pmids\": [\"22072986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular step at which LZTFL1 blocks BBSome entry\", \"Smoothened readout was correlative localization rather than direct binding\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Confirmed in human loss-of-function cells that LZTFL1 is a negative regulator of Shh signaling, validating the ciliopathy-relevant pathway consequence of its loss.\",\n      \"evidence\": \"Western blot and RT-PCR of Smoothened, Patched1, and GLI2 in patient fibroblasts carrying a frameshift deletion\",\n      \"pmids\": [\"22510444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient genotype\", \"Did not distinguish direct ciliary trafficking effects from secondary transcriptional changes\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a cilium-independent role: LZTFL1 sequesters β-catenin in the cytoplasm to suppress EMT, broadening its function into Wnt-associated tumor suppression.\",\n      \"evidence\": \"Reciprocal Co-IP, in situ proximity ligation, and migration/invasion/zymography assays in gastric cancer cells\",\n      \"pmids\": [\"25005785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface on β-catenin not mapped\", \"Single cancer cell context\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the EMT-suppressive role to lung epithelium and demonstrated in vivo tumor suppression, tying LZTFL1 to ciliated-cell differentiation and TGF-β/MAPK/Hedgehog signaling.\",\n      \"evidence\": \"Re-expression in tumor lines, pathway Western blots, and in vivo colonization assays in mice\",\n      \"pmids\": [\"26364604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Multiple pathways implicated without defining the primary direct target\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a role in immune cells, showing LZTFL1 redistributes to the immunological synapse and tunes TCR-mediated NFAT signaling and cytokine output.\",\n      \"evidence\": \"Live-cell imaging, knockdown/overexpression, NFAT luciferase reporter, and cytokine ELISA in CD4+ T cells\",\n      \"pmids\": [\"26700766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners at the synapse not identified\", \"Connection to ciliary trafficking machinery unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the in vivo ciliary phenotype of LZTFL1 loss, showing it regulates BBSome ciliary content and is required for photoreceptor outer segment integrity and protein sorting.\",\n      \"evidence\": \"Lztfl1 knockout mice with immunofluorescence, fractionation, TUNEL, and electron microscopy of photoreceptors\",\n      \"pmids\": [\"27312011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking AP1 adaptor increase to rhodopsin mislocalization not resolved\", \"Single model organism readout\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed LZTFL1 in hypothalamic leptin signaling, showing its loss abolishes leptin-stimulated STAT3 phosphorylation and drives obesity through a brain-specific requirement.\",\n      \"evidence\": \"Global and tissue-specific knockout mice, leptin-stimulated STAT3 phosphorylation Western blots, cilia measurement, and Co-IP\",\n      \"pmids\": [\"30423168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Step at which LZTFL1 couples LepRb to STAT3 not defined\", \"Actin/cytoskeleton interactors not individually validated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the dual molecular mechanism of LZTFL1 in BBSome dynamics — basal-body recruitment via BBS3/ARL6 and tip reassembly via IFT25/27 stabilization — using a tractable ciliary genetic system.\",\n      \"evidence\": \"Chlamydomonas genetics, IFT imaging assays, Co-IP, and combinatorial mutant epistasis\",\n      \"pmids\": [\"34446551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of the exact dual mechanism in mammalian cilia not fully demonstrated\", \"Structural basis of BBS3 and IFT25/27 binding unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed in vivo that LZTFL1 specifically stabilizes IFT27, linking its trafficking function to flagellar assembly and male fertility.\",\n      \"evidence\": \"Knockout mouse with selective loss of testicular IFT27, sperm motility analysis, and in vitro fertilization\",\n      \"pmids\": [\"34023333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LZTFL1–IFT27 binding interface not mapped\", \"Whether stabilization is via direct binding or pathway effect unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified how the 3p21.31 COVID-19 risk locus acts, showing the risk allele enhancer upregulates LZTFL1 in association with EMT activation in patient lung epithelium.\",\n      \"evidence\": \"Chromosome conformation capture, expression analysis, and spatial transcriptomics of patient biopsies with machine learning\",\n      \"pmids\": [\"34737427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from LZTFL1 upregulation to disease severity not experimentally dissected\", \"EMT association is correlative in tissue\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a post-transcriptional control mechanism, showing the SNHG6 lncRNA recruits PTBP1 to destabilize LZTFL1 mRNA in hepatoma cells.\",\n      \"evidence\": \"Quantitative proteomics, RNA immunoprecipitation, and mRNA stability assays\",\n      \"pmids\": [\"34252487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of LZTFL1 loss in this context not fully traced\", \"Single cancer model\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Functionally confirmed that the COVID-19 GWAS locus regulates LZTFL1 transcription, validating LZTFL1 as the causal gene at the locus.\",\n      \"evidence\": \"CRISPRi targeting near rs11385942 in intron 5 with qRT-PCR in lung epithelial cell lines\",\n      \"pmids\": [\"34998241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream phenotypic effect of reduced LZTFL1 not measured here\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a proliferation-control mechanism, showing LZTFL1 destabilizes AKT through the ZNRF1 ubiquitin-proteasome pathway to enforce G1 arrest.\",\n      \"evidence\": \"Gain/loss-of-function in kidney tumor lines, PDX rescue, AKT Western blots, and cell cycle analysis\",\n      \"pmids\": [\"36966254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LZTFL1–ZNRF1 interaction not structurally characterized\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked LZTFL1 to canonical Wnt/β-catenin signaling and adipogenesis, showing its loss in MSCs suppresses Wnt activation and favors fat differentiation.\",\n      \"evidence\": \"Knockout MSCs analyzed by Western blot, flow cytometry, lipid-raft fractionation, and cell-surface LRP6 assay\",\n      \"pmids\": [\"39662832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting LZTFL1 to CAV1/LRP6 raft organization unresolved\", \"Single cell system\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated LZTFL1 in Th2 differentiation via an ERK/GATA3 axis in allergic airway inflammation.\",\n      \"evidence\": \"Lentiviral shRNA knockdown in an OVA asthma mouse model with Western blot, flow cytometry, and cytokine ELISA\",\n      \"pmids\": [\"38310669\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"ERK→GATA3 protein stabilization not directly demonstrated\", \"Mechanism inferred indirectly\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LZTFL1's conserved ciliary trafficking function mechanistically connects to its many non-ciliary roles (β-catenin, AKT/ZNRF1, leptin/STAT3, ERK/GATA3) remains unresolved, as does the structural basis of its interactions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of LZTFL1 with BBSome, BBS3, or IFT25/27\", \"Whether cytoplasmic signaling roles are separable from ciliary trafficking unknown\", \"No unifying biochemical activity defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009579\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"complexes\": [\"BBSome\"],\n    \"partners\": [\"BBS3\", \"ARL6\", \"IFT27\", \"IFT25\", \"CTNNB1\", \"ZNRF1\", \"PTBP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}