Affinage

Showing LTO1 — ORAOV1 is a alias.

LTO1

Protein LTO1 homolog · UniProt Q8WV07

Length
137 aa
Mass
15.4 kDa
Annotated
2026-06-10
21 papers in source corpus 8 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LTO1 (ORAOV1) is a target-specific adaptor for iron-sulfur (Fe-S) cluster delivery that couples the cytosolic Fe-S assembly (CIA) machinery to the ribosome-recycling/translation factor ABCE1/Rli1, thereby supporting 60S ribosomal subunit maturation and translation initiation under aerobic conditions (PMID:23318452, PMID:26182403). It forms a heterodimer with YAE1 in which deca-GX3 motifs in both proteins mediate their interaction, LTO1 uses a conserved C-terminal tryptophan to engage the CIA targeting complex, and YAE1 bridges recruitment of apo-ABCE1/Rli1 for Fe-S insertion; depletion of either adaptor selectively impairs Fe-S maturation of Rli1 but not other CIA targets (PMID:23318452, PMID:26182403). This adaptor function is evolutionarily conserved, as human ORAOV1 and YAE1D1 functionally replace their yeast counterparts (PMID:26182403). Through its control of ABCE1, the LTO1/YAE1 axis is required for nonsense-mediated mRNA decay (NMD), and loss of this axis impairs NMD, derepressing MHC-I regulators NLRC5, IRF1, and NF-κB to enhance T cell-mediated tumor killing (PMID:40987494). In cancer cells ORAOV1 additionally binds pyrroline-5-carboxylate reductase (PYCR) to raise intracellular proline and lower reactive oxygen species, and acts as an 11q13-amplicon oncogenic driver promoting cell cycle progression, survival, and tumor angiogenesis (PMID:24930674, PMID:18688849, PMID:37930255).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2013 High

    Established the core cellular function of LTO1 by showing it is specifically required for 60S subunit maturation and aerobic translation initiation, linking it to ribosome biogenesis under oxidative conditions.

    Evidence Conditional yeast YNL260c mutants with ribosomal maturation and translation assays, plus human ORAOV1 complementation

    PMID:23318452

    Open questions at the time
    • Did not yet define the molecular mechanism connecting LTO1 to 60S maturation
    • Oxygen-dependence mechanism inferred rather than directly demonstrated
  2. 2013 High

    Identified the physical partners of LTO1, showing it assembles with YAE1 and the Fe-S-bearing ATPase Rli1/ABCE1, with YAE1 bridging the LTO1-Rli1 interaction.

    Evidence In vivo co-immunoprecipitation and in vitro binding assays

    PMID:23318452

    Open questions at the time
    • Did not define which residues mediate complex assembly
    • Functional consequence of the interaction for Fe-S loading not yet shown
  3. 2015 High

    Resolved the mechanism by defining LTO1/YAE1 as a target-specific CIA adaptor that delivers Fe-S clusters selectively to apo-Rli1/ABCE1, via a C-terminal tryptophan and deca-GX3 motifs.

    Evidence Systematic interaction mapping, Yae1/Lto1 depletion with Fe-S maturation assays, tryptophan mutagenesis, and human gene complementation

    PMID:26182403

    Open questions at the time
    • Structural basis of CIA-targeting-complex recognition not resolved
    • Whether additional targets exist beyond Rli1 not exhaustively tested
  4. 2015 High

    Demonstrated evolutionary conservation by showing human ORAOV1 and YAE1D1 substitute for yeast Lto1/Yae1 in the Fe-S delivery pathway.

    Evidence Cross-species genetic complementation in yeast deletion strains

    PMID:26182403

    Open questions at the time
    • Conservation of the human pathway not validated directly in human cells in this work
  5. 2025 High

    Connected the LTO1/YAE1/ABCE1 axis to a downstream physiological output by showing it is required for NMD, and that its loss derepresses MHC-I and enhances anti-tumor immunity.

    Evidence CRISPR KO/overexpression, NMD reporter and mRNA decay assays, polysome profiling, TCR-T coculture, and in vivo tumor models

    PMID:40987494

    Open questions at the time
    • Direct biochemical step in NMD requiring ABCE1 Fe-S not isolated
    • How iron chelators inhibit the axis mechanistically not fully resolved
  6. 2014 Medium

    Linked ORAOV1 to redox homeostasis in cancer by showing it binds PYCR to elevate proline and reduce ROS, conferring stress resistance.

    Evidence MS-based co-purification, PYCR knockdown rescue, and proline/ROS measurements in esophageal cancer cells

    PMID:24930674

    Open questions at the time
    • Single lab; PYCR interaction not reciprocally validated
    • Relationship between this metabolic role and the Fe-S adaptor role unclear
  7. 2008 Medium

    Defined ORAOV1 as a pro-proliferative, anti-apoptotic, and pro-angiogenic factor in oral squamous cell carcinoma.

    Evidence siRNA knockdown with cell cycle, apoptosis, xenograft, and VEGF assays

    PMID:18688849

    Open questions at the time
    • Molecular link between adaptor function and cell cycle phenotype not established
    • Effects could be indirect consequences of impaired translation
  8. 2010 Medium

    Replicated and extended the cancer phenotype in a second cell type, mapping ORAOV1 loss to S-phase arrest and activation of both apoptotic pathways.

    Evidence siRNA knockdown with cell cycle analysis and apoptosis pathway Western blots in HeLa cells

    PMID:20105337

    Open questions at the time
    • Mechanism connecting ORAOV1 to cyclin/caspase regulation not defined
    • Single lab
  9. 2017 Medium

    Identified ORAOV1 as an anti-apoptotic host factor targeted for degradation by IBDV VP2 during viral infection.

    Evidence Co-IP and bidirectional gain/loss-of-function with apoptosis and viral release assays in avian cells

    PMID:28769911

    Open questions at the time
    • Mechanism of VP2-induced degradation not defined
    • Relevance to mammalian/human biology unclear
  10. 2024 Medium

    Validated ORAOV1 as a bona fide oncogenic driver within the 11q13 amplicon in squamous cell carcinoma, acting via ROS modulation.

    Evidence CRISPR-Cas9 KO in primary human keratinocytes with in vitro, ex vivo, and in vivo models plus ROS measurement

    PMID:37930255

    Open questions at the time
    • ROS mechanism inferred rather than reconstituted
    • Whether the oncogenic effect operates through the Fe-S adaptor role unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LTO1's conserved Fe-S adaptor function mechanistically integrates with its observed redox, cell cycle, and oncogenic roles in cancer remains unresolved.
  • No structural model of the human ORAOV1/YAE1D1/ABCE1 complex
  • Unclear whether cancer phenotypes derive from impaired ABCE1 Fe-S loading or separate activities

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 1 R-HSA-392499 Metabolism of proteins 1 R-HSA-8953854 Metabolism of RNA 1
Partners
ABCE1PYCRYAE1
Complex memberships
CIA targeting complex (associated)LTO1-YAE1 adaptor complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 LTO1 (yeast YNL260c, ortholog of ORAOV1) is required for maturation of the 60S ribosomal subunit but not the 40S subunit, and for initiation of translation under aerobic conditions; loss of LTO1 function is lethal in oxygen but not under anaerobic conditions, linking its essential role to protection of ribosome biogenesis from reactive oxygen species. Conditional yeast mutants of YNL260c; ribosomal subunit maturation assays; translation initiation assays; complementation by human ORAOV1 Oncogene High 23318452
2013 LTO1 forms a complex with Rli1/ABCE1 (an ABC-ATPase bearing N-terminal [4Fe-4S] clusters) and Yae1; Yae1 bridges the interaction between Lto1 and Rli1/ABCE1; interactions were demonstrated both in vivo and in vitro. In vivo co-immunoprecipitation and in vitro binding assays Oncogene High 23318452
2015 Yae1 and Lto1 function as target-specific adaptors for iron-sulfur (Fe-S) cluster insertion into Rli1/ABCE1: Lto1 uses its conserved C-terminal tryptophan to bind the CIA targeting complex, deca-GX3 motifs in both Yae1 and Lto1 mediate their heterocomplex formation, and Yae1 recruits apo-Rli1 to the CIA machinery. Depletion of Yae1 or Lto1 causes defective Fe-S maturation of Rli1 but not other tested CIA targets. Systematic protein interaction approaches (Co-IP, pulldown); depletion of Yae1/Lto1 followed by Fe-S maturation assays; C-terminal tryptophan mutagenesis; complementation with human YAE1D1 and ORAOV1 eLife High 26182403
2015 Human ORAOV1 (LTO1) and YAE1D1 can functionally replace their yeast counterparts Lto1 and Yae1, demonstrating evolutionary conservation of their role in the CIA/Rli1 Fe-S assembly pathway. Complementation assay: expression of human genes in yeast deletion strains eLife High 26182403
2014 ORAOV1 binds to pyrroline-5-carboxylate reductase (PYCR), leading to increased intracellular proline concentration and lower ROS levels; PYCR knockdown reverses the stress-resistance phenotype of ORAOV1-overexpressing esophageal cancer cells. Peptide mass fingerprinting (co-purification/MS); PYCR knockdown rescue assay; intracellular proline and ROS measurements Oncotarget Medium 24930674
2008 siRNA-mediated knockdown of ORAOV1 in oral squamous cell carcinoma cells causes S-phase cell cycle arrest with downregulation of cyclin A, cyclin B1, and CDC2, and activates caspase-3-dependent apoptosis; in vivo, ORAOV1 knockdown inhibits tumor growth and suppresses VEGF-dependent tumor angiogenesis. siRNA knockdown; cell cycle analysis; apoptosis assays; xenograft tumor model; VEGF measurement International journal of cancer Medium 18688849
2010 Knockdown of ORAOV1 in HeLa cervical cancer cells causes S-phase arrest with downregulation of Cyclin A, Cyclin B1, CDC2, and Cyclin D1, and activates both extrinsic (Caspase-8) and intrinsic (Caspase-9, cytochrome c) apoptotic pathways, with altered P53 and Bcl-2 expression. siRNA knockdown; cell cycle analysis; apoptosis pathway protein analysis by Western blot Molecular cancer Medium 20105337
2017 IBDV VP2 protein interacts with ORAOV1 and causes its degradation; ORAOV1 reduction mediates VP2-induced apoptosis, whereas ORAOV1 overexpression inhibits VP2/IBDV-induced apoptosis and restricts viral release, identifying ORAOV1 as an antiapoptotic molecule. Co-immunoprecipitation (VP2–ORAOV1 interaction); overexpression and knockdown of ORAOV1; apoptosis and viral release assays Frontiers in microbiology Medium 28769911
2024 ORAOV1 functions as an oncogenic driver in the 11q13 amplicon in squamous cell carcinoma, acting likely via modulation of reactive oxygen species, as identified by computational, in vitro, ex vivo, and in vivo models using primary human keratinocyte Cas9-RNP genome editing. CRISPR-Cas9 KO in primary human keratinocytes; in vitro, ex vivo, in vivo models; ROS measurement Molecular cancer research : MCR Medium 37930255
2025 The LTO1/YAE1 complex regulates nonsense-mediated mRNA decay (NMD); deficiency in LTO1, YAE1, or their downstream target ABCE1 impairs NMD, leading to overexpression of MHC-I regulators NLRC5, IRF1, and NF-κB, enhanced T cell activation, and tumor cell killing. Iron chelators, by inhibiting NMD via the LTO1/YAE1/ABCE1 axis, enhance MHC-I expression and improve anti-tumor immune responses. CRISPR-Cas9 KO and overexpression; fluorescent NMD reporter assays; FACS; RT-qPCR; mRNA decay assays; polysome profiling; TCR-T cell coculture; in vivo mouse tumor model Journal for immunotherapy of cancer High 40987494

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 High-resolution mapping of the 11q13 amplicon and identification of a gene, TAOS1, that is amplified and overexpressed in oral cancer cells. Proceedings of the National Academy of Sciences of the United States of America 171 12172009
2007 Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nature genetics 156 17906623
2003 Evolutionary conservation of CCND1-ORAOV1-FGF19-FGF4 locus from zebrafish to human. International journal of molecular medicine 116 12792807
2015 The deca-GX3 proteins Yae1-Lto1 function as adaptors recruiting the ABC protein Rli1 for iron-sulfur cluster insertion. eLife 53 26182403
2014 Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production. Oncotarget 52 24930674
2008 Oral cancer overexpressed 1 (ORAOV1): a regulator for the cell growth and tumor angiogenesis in oral squamous cell carcinoma. International journal of cancer 48 18688849
2006 Amplifications of TAOS1 and EMS1 genes in oral carcinogenesis: association with clinicopathological features. Oral oncology 39 17005439
2010 Oral cancer overexpressed 1 (ORAOV1) regulates cell cycle and apoptosis in cervical cancer HeLa cells. Molecular cancer 35 20105337
2013 The function of ORAOV1/LTO1, a gene that is overexpressed frequently in cancer: essential roles in the function and biogenesis of the ribosome. Oncogene 34 23318452
2017 VP2 of Infectious Bursal Disease Virus Induces Apoptosis via Triggering Oral Cancer Overexpressed 1 (ORAOV1) Protein Degradation. Frontiers in microbiology 25 28769911
2021 ORAOV1-B Promotes OSCC Metastasis via the NF-κB-TNFα Loop. Journal of dental research 23 33655785
2006 TAOS1, a novel marker for advanced esophageal squamous cell carcinoma. Anticancer research 23 16827140
2009 ORAOV1-A correlates with poor differentiation in oral cancer. Journal of dental research 13 19493886
2011 ORAOV1 is a probable target within the 11q13.3 amplicon in lymph node metastases from gastric adenocarcinoma. International journal of molecular medicine 12 21993861
2011 ORAOV1 is amplified in oral squamous cell carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 10 21623924
2014 Identification of potential targets for thylakoid oxidoreductase AtVKOR/LTO1 in chloroplasts. Protein and peptide letters 7 25412899
2024 ORAOV1, CCND1, and MIR548K Are the Driver Oncogenes of the 11q13 Amplicon in Squamous Cell Carcinoma. Molecular cancer research : MCR 5 37930255
2020 Validation of ORAOV1 as a new treatment target in hepatocellular carcinoma. Journal of cancer research and clinical oncology 4 33161447
2015 RNAi-mediated downregulation of oral cancer overexpressed 1 (ORAOV1) inhibits vascular endothelial cell proliferation, migration, invasion, and tube formation. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 3 26449957
2025 LTO1 and YAE1 regulate MHC-I expression via nonsense-mediated RNA decay in tumor cells. Journal for immunotherapy of cancer 0 40987494
2025 Overexpression of ORAOV1 and its association with immunotherapy resistance in hepatocellular carcinoma. PeerJ 0 41321947

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