Affinage

LZTFL1

Leucine zipper transcription factor-like protein 1 · UniProt Q9NQ48

Length
299 aa
Mass
34.6 kDa
Annotated
2026-04-28
24 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2011 High

    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

    PMID:22072986

    Open questions at the time
    • 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
  2. 2012 Medium

    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

    PMID:22510444

    Open questions at the time
    • Based on a single patient genotype; broader patient cohort not examined
    • Downstream transcriptional consequences (GLI target gene panel) not comprehensively profiled
  3. 2014 High

    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

    PMID:25005785

    Open questions at the time
    • Whether LZTFL1–β-catenin binding is direct or mediated by an adaptor not resolved
    • Structural basis of the interaction unknown
  4. 2015 Medium

    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

    PMID:26364604

    Open questions at the time
    • Whether LZTFL1 directly engages TGF-β receptor components or acts indirectly not determined
    • Single-lab in vivo colonization model
  5. 2016 High

    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

    PMID:27312011

    Open questions at the time
    • Mechanism linking LZTFL1 loss to AP1 mislocalization in photoreceptors not elucidated
    • Whether photoreceptor degeneration is cell-autonomous not fully resolved
  6. 2018 High

    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

    PMID:30423168

    Open questions at the time
    • Molecular step at which LZTFL1 enables LepRb–STAT3 coupling not identified
    • Whether the metabolic phenotype is cilium-dependent or cilium-independent not distinguished
  7. 2019 High

    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

    PMID:31351450

    Open questions at the time
    • Whether other miRNAs redundantly target LZTFL1 not explored
    • Tissue specificity of miR-21 regulation of LZTFL1 not addressed
  8. 2021 High

    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

    PMID:34446551

    Open questions at the time
    • Whether the dual-control model fully applies in mammalian cilia not confirmed
    • Biochemical basis of LZTFL1-dependent IFT25/27 stabilization unknown
  9. 2021 High

    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

    PMID:34023333

    Open questions at the time
    • Whether IFT27 instability is the sole cause of flagellar defects not determined
    • Rescue by IFT27 re-expression not performed
  10. 2021 High

    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

    PMID:34737427 PMID:34998241

    Open questions at the time
    • 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
  11. 2023 Medium

    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

    PMID:36966254

    Open questions at the time
    • Whether LZTFL1 acts as a scaffold bridging ZNRF1 to AKT or has a separate role not resolved
    • Generalizability beyond ccRCC not tested
  12. 2024 Medium

    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

    PMID:39662832

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005929 cilium 3 GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-1266738 Developmental Biology 2 R-HSA-392499 Metabolism of proteins 1
Partners
BBS3BBS5BBS9CTNNB1IFT27PTBP1ZNRF1
Complex memberships
BBSome

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. Co-immunoprecipitation, siRNA knockdown, fluorescence microscopy of ciliary localization, genetic epistasis in cell lines PLoS genetics High 22072986
2012 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. Immunofluorescence and protein expression analysis in patient-derived fibroblasts with homozygous LZTFL1 deletion Journal of medical genetics Medium 22510444
2014 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. Co-immunoprecipitation, Duolink in situ proximity ligation assay, Transwell migration/invasion assay, gelatin zymography, LZTFL1 knockdown/overexpression Journal of cancer research and clinical oncology High 25005785
2015 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. LZTFL1 knockdown/re-expression in NSCLC lines, Western blotting for pathway components, in vivo mouse colonization assay Oncogene Medium 26364604
2015 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. Live-cell imaging, immunofluorescence, siRNA knockdown, LZTFL1 overexpression, NFAT reporter assay, cytokine ELISA Journal of immunology Medium 26700766
2016 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. Lztfl1 knockout mouse model, immunofluorescence, TUNEL assay, electron microscopy, subcellular fractionation Journal of genetics and genomics High 27312011
2018 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. Conditional Lztfl1 knockout mouse, phospho-STAT3 Western blotting, leptin stimulation assay, tissue-specific deletion, primary cilia length measurement, Co-IP interactome Journal of molecular cell biology High 30423168
2019 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. Luciferase 3′ UTR reporter assay, siRNA knockdown, colony formation, Transwell and wound-healing assays, in vivo mouse tumor model BMC cancer High 31351450
2021 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. Chlamydomonas LZTFL1 mutant analysis, fluorescence microscopy of BBSome and IFT component localization, phototaxis behavioral assay, genetic rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 34446551
2021 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. Lztfl1 knockout mouse, sperm motility analysis, in vitro fertilization assay, Western blotting, immunofluorescence localization Developmental biology High 34023333
2021 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. Chromosome conformation capture (3C/Hi-C), gene expression analysis, spatial transcriptomics of patient lung biopsies, multiomics + machine learning Nature genetics High 34737427
2021 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. Quantitative proteomics, RNA immunoprecipitation, siRNA knockdown, mRNA stability assays, epistasis rescue experiments Cancer letters Medium 34252487
2022 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. CRISPRi-mediated gene expression knockdown in lung epithelial cell lines, qRT-PCR EBioMedicine Medium 34998241
2023 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. 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 Oncogene Medium 36966254
2024 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. Lztfl1 knockout mouse, CB-MSC isolation and differentiation assay, Western blotting, flow cytometry, lipid raft fractionation, immunofluorescence The Journal of biological chemistry Medium 39662832
2011 Overexpression of Lztfl1 in Neuro 2a neuronal cells promotes neurite outgrowth, indicating a role for LZTFL1 in neuronal differentiation. Lztfl1 overexpression in Neuro 2a cells, morphological analysis of neurite length Biochemical and biophysical research communications Low 22093827

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 microRNA-21 promotes breast cancer proliferation and metastasis by targeting LZTFL1. BMC cancer 213 31351450
2011 A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened. PLoS genetics 164 22072986
2021 Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus. Nature genetics 112 34737427
2012 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. Journal of medical genetics 102 22510444
2015 LZTFL1 suppresses lung tumorigenesis by maintaining differentiation of lung epithelial cells. Oncogene 43 26364604
2013 Mesoaxial polydactyly is a major feature in Bardet-Biedl syndrome patients with LZTFL1 (BBS17) mutations. Clinical genetics 31 23692385
2001 The LZTFL1 gene is a part of a transcriptional map covering 250 kb within the common eliminated region 1 (C3CER1) in 3p21.3. Genomics 31 11352561
2016 Depletion of BBS Protein LZTFL1 Affects Growth and Causes Retinal Degeneration in Mice. Journal of genetics and genomics = Yi chuan xue bao 30 27312011
2014 LZTFL1 suppresses gastric cancer cell migration and invasion through regulating nuclear translocation of β-catenin. Journal of cancer research and clinical oncology 30 25005785
2021 lncRNA SNHG6 promotes hepatocellular carcinoma progression by interacting with HNRNPL/PTBP1 to facilitate SETD7/LZTFL1 mRNA destabilization. Cancer letters 27 34252487
2015 LZTFL1 Upregulated by All-Trans Retinoic Acid during CD4+ T Cell Activation Enhances IL-5 Production. Journal of immunology (Baltimore, Md. : 1950) 27 26700766
2022 CRISPRi links COVID-19 GWAS loci to LZTFL1 and RAVER1. EBioMedicine 21 34998241
2018 Lztfl1/BBS17 controls energy homeostasis by regulating the leptin signaling in the hypothalamic neurons. Journal of molecular cell biology 20 30423168
2022 Host genetic loci LZTFL1 and CCL2 associated with SARS-CoV-2 infection and severity of COVID-19. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 17 35753602
2021 Chlamydomonas LZTFL1 mediates phototaxis via controlling BBSome recruitment to the basal body and its reassembly at the ciliary tip. Proceedings of the National Academy of Sciences of the United States of America 17 34446551
2021 Leucine zipper transcription factor-like 1 (LZTFL1), an intraflagellar transporter protein 27 (IFT27) associated protein, is required for normal sperm function and male fertility. Developmental biology 12 34023333
2011 Involvement of leucine zipper transcription factor-like protein 1 (Lztfl1) in the attenuation of cognitive impairment by exercise training. Biochemical and biophysical research communications 9 22093827
2024 Aberrant Wnt/β-catenin signaling in the mesenchymal stem cells of LZTFL1-depleted mice leads to increased adipogenesis, with implications for obesity. The Journal of biological chemistry 6 39662832
2023 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. American journal of cancer research 5 37424811
2023 ABCA3 and LZTFL1 Polymorphisms and Risk of COVID-19 in the Czech Population. Physiological research 5 37795896
2024 Anti-inflammation of LZTFL1 knockdown in OVA-induced asthmatic mice: Through ERK/GATA3 signaling pathway. Molecular immunology 4 38310669
2023 LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway. Oncogene 4 36966254
2019 Tumor suppressive functions of LZTFL1 in hepatocellular carcinoma. OncoTargets and therapy 3 31371991
2024 LZTFL1, a rare cause of Bardet-Biedl syndrome: A new patient with severe short stature and moderate intellectual disability, more than casual associations? American journal of medical genetics. Part A 0 38801250