Affinage

LTV1

Protein LTV1 homolog · UniProt Q96GA3

Length
475 aa
Mass
54.9 kDa
Annotated
2026-06-10
12 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LTV1 is a conserved 40S ribosome biogenesis assembly factor that binds nascent pre-40S particles and chaperones the hierarchical maturation of the small subunit head (PMID:16888326, PMID:30348748, PMID:37910572). It directly binds several head ribosomal proteins and facilitates the ordered incorporation of Rps3, Rps10, and Asc1/RACK1, while simultaneously delaying the recruitment of other proteins, thereby controlling the timing of both RP assembly and the acquisition of the rRNA structures those proteins stabilize; it also directly chaperones folding of the j34-35-38 three-helix junction in rRNA (PMID:30348748, PMID:37910572). Ribosomes formed in the absence of LTV1 are substoichiometric for Rps10 and Asc1 and show defects in translational fidelity and ribosome-mediated RNA quality control (PMID:30348748). Release of Ltv1 from nascent pre-40S subunits is triggered by phosphorylation by Hrr25 (the yeast CK1δ/ε homolog), a step required for subunit maturation and entry into the translation-like quality control cycle (PMID:25778921). Ltv1 additionally serves as a Crm1-dependent nuclear export adapter for the small subunit through a C-terminal leucine-rich NES, but this export function is redundant with other adapters at endogenous expression levels (PMID:16888326, PMID:25213169). Across species the protein supports growth-coupled ribosome production — in Drosophila it is a direct dMyc transcriptional target required for Myc-driven ribosome biogenesis and cell growth (PMID:25858587) — and a loss-of-function splicing variant in human LTV1 causes the LIPHAK ribosomopathy syndrome (PMID:34999892, PMID:37910572).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 Medium

    Established that Ltv1 is a bona fide 40S production factor rather than a generic ribosome-associated protein, by showing it physically partners with RpS3/Yar1 in a pre-40S complex and its loss selectively reduces 40S subunits.

    Evidence Co-immunoprecipitation, polysome profiling, and genetic suppression in yeast

    PMID:15611164

    Open questions at the time
    • Did not define the molecular step Ltv1 performs in assembly
    • RpS3 overexpression failed to suppress, leaving Ltv1's distinct function unexplained
  2. 2006 High

    Identified a nuclear export role by showing Ltv1 shuttles in a Crm1-dependent manner via a functional NES and links the export machinery to the small subunit, addressing how pre-40S particles reach the cytoplasm.

    Evidence Sucrose gradient co-sedimentation, shuttling/export reporter assay, FISH localization, and YRB2 genetic interaction in yeast

    PMID:16888326

    Open questions at the time
    • Did not establish whether the export adapter role is the essential function of Ltv1
    • Cytoplasmic maturation steps not resolved
  3. 2010 Medium

    Showed that Ltv1 is required for cytoplasmic maturation of 40S subunits and that nuclear retention of pre-40S in NES-defective mutants is a downstream consequence of failed factor recycling, refining the order of events.

    Evidence Dominant-negative NES mutagenesis, FISH, GFP-tagged RP imaging, and sedimentation in yeast

    PMID:20215468

    Open questions at the time
    • Mechanism triggering Ltv1 release from the subunit unknown
    • Did not separate export from cytoplasmic maturation contributions
  4. 2014 Medium

    Resolved the significance of the export function by mapping a canonical C-terminal NES and showing that at endogenous levels its export adapter role is fully redundant, with RpS3 titration explaining the dominant-negative phenotype.

    Evidence NES mutagenesis, Crm1 interaction assay, functional NES substitution for Nmd3, and genetic suppression in yeast

    PMID:25213169

    Open questions at the time
    • Did not identify the redundant export adapters
    • Essential, non-redundant function of Ltv1 remained undefined
  5. 2015 High

    Defined the regulatory trigger for Ltv1 release by showing Hrr25/CK1δ phosphorylation drives its dissociation and licenses maturation, and connected this to the antiproliferative action of CK1 inhibitors in human cancer cells.

    Evidence In vitro kinase assay, non-phosphorylatable and phosphomimetic mutants, genetic rescue in yeast, and siRNA knockdown/viability in human breast cancer cells

    PMID:25778921

    Open questions at the time
    • Did not map which Ltv1 residues are phosphorylated structurally
    • How phosphorylation alters Ltv1-subunit contacts not resolved
  6. 2015 Medium

    Placed LTV1 in a growth-control circuit by showing the Drosophila ortholog is a direct dMyc transcriptional target required for Myc-driven ribosome biogenesis and cell growth.

    Evidence Co-IP, sucrose gradient fractionation, pre-rRNA processing, dMyc ChIP/reporter, and loss-of-function epistasis in Drosophila

    PMID:25858587

    Open questions at the time
    • Whether Myc regulates LTV1 in mammals not tested
    • Conservation of the growth-coupling circuit to humans unaddressed
  7. 2018 High

    Defined the chaperone mechanism by demonstrating Ltv1 facilitates incorporation of Rps3, Rps10, and Asc1/RACK1 into the head, with functional consequences for translational fidelity and a link to altered ribosome composition in cancer cells.

    Evidence Yeast deletion genetics, quantitative MS of ribosome composition, rRNA structure probing, translational fidelity assays, and human cancer cell line analysis

    PMID:30348748

    Open questions at the time
    • Direct vs indirect contributions to each RP not separated
    • Structural basis of head chaperoning not yet mapped
  8. 2022 Medium

    Established LTV1 as a human disease gene by showing a homozygous splice-altering variant produces a loss-of-function allele underlying the LIPHAK ribosomopathy syndrome.

    Evidence Whole-genome sequencing, homozygosity mapping, and minigene splicing assay in HEK293T and patient tissue

    PMID:34999892

    Open questions at the time
    • Did not connect the variant to a specific molecular ribosome assembly defect
    • Genotype-phenotype basis of LIPHAK features not mechanistically explained
  9. 2023 High

    Provided a mechanistic model of hierarchical assembly control by showing Ltv1 directly binds 5 head RPs, delays recruitment of others, and chaperones a specific rRNA three-helix junction, and connected the disease mutation to global head assembly defects.

    Evidence Yeast genetics, MS, DMS chemical rRNA probing, biochemical interaction assays, and disease-mutant analysis

    PMID:37910572

    Open questions at the time
    • High-resolution structure of the Ltv1-pre-40S complex not reported
    • How delayed RP recruitment is mechanistically enforced not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LTV1 loss-of-function gives rise to the specific tissue phenotypes of LIPHAK, and whether its head-assembly chaperone role couples to oncogenic ribosome heterogeneity in human tissues, remains open.
  • No structural model of the human LTV1-pre-40S complex
  • Tissue-specific consequences of altered ribosome composition unresolved
  • Direct link between LIPHAK variant and translational defects in patients not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 2 GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9609507 Protein localization 2
Partners
CRM1HRR25RACK1RPS10RPS3YAR1
Complex memberships
pre-40S ribosomal particle

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Ltv1 shuttles between nucleus and cytoplasm in a Crm1-dependent manner and contains a functional nuclear export sequence (NES) sufficient to direct export of an NLS-containing reporter. Ltv1 co-sediments with 43S/40S subunits and copurifies with late 43S particles. Loss of LTV1 reduces small subunit export as judged by altered distribution of 5'-ITS1 rRNA and RpS3. Genetic interaction was identified between LTV1 and YRB2 (a Ran-GTP/Crm1-binding protein), placing Ltv1 as an adapter linking nuclear export machinery to the small subunit. Sucrose gradient co-sedimentation, copurification, shuttling assay (heterokaryon/reporter), FISH/fluorescence localization, genetic interaction analysis Genetics High 16888326
2004 Ltv1 physically interacts with Yar1 (an ankyrin-repeat protein) and RpS3 as part of a pre-40S complex. Loss of LTV1 results in reduced absolute numbers of 40S subunits and excess free 60S subunits, indicating a role in 40S subunit production. Overexpression of RPS3 does not suppress the ribosome biogenesis defect of Δltv1, distinguishing Ltv1's role from that of Yar1. Co-immunoprecipitation, polysome profiling, genetic suppression analysis Genetics Medium 15611164
2010 Mutation or deletion of the putative NES in Ltv1 is strongly dominant negative; the dominant-negative mutant protein accumulates in the cytoplasm associated with pre-40S subunits, causes accumulation of 20S rRNA in the cytoplasm (detected by FISH), retains late biogenesis factor Tsr1 in the cytoplasm, and leads to nuclear retention of 40S markers (RpS2-GFP, RpS3-GFP). This places Ltv1 as required for cytoplasmic maturation of 40S subunits, with nuclear retention of pre-40S being a downstream consequence of failure to recycle factors. Dominant-negative mutagenesis, FISH, fluorescence microscopy (GFP-tagged ribosomal proteins), sucrose gradient sedimentation Genetics Medium 20215468
2014 Ltv1 has a canonical leucine-rich NES at its extreme C-terminus that is both necessary for Crm1 interaction and for Ltv1 nuclear export. The C-terminus can functionally substitute for the NES of the 60S-export adapter Nmd3. However, deletion of the NES at endogenous levels complements slow growth and 40S biogenesis defects, suggesting Ltv1's export adapter function is fully redundant with other factors. Dominant-negative phenotype of NES-deleted Ltv1 overexpression is suppressed by co-overexpression of RpS3 and its chaperone Yar1, or by deleting the RpS3-binding site in Ltv1ΔNES, indicating that titration of RpS3 by excess nuclear Ltv1 is the deleterious mechanism. NES mutagenesis, Crm1 interaction assay, functional NES substitution, genetic suppression, overexpression complementation Genetics Medium 25213169
2015 Hrr25 (yeast CK1δ/ε homolog) phosphorylates Ltv1, causing its release from nascent pre-40S subunits and allowing subunit maturation. Hrr25 inactivation or expression of a non-phosphorylatable Ltv1 variant blocked Ltv1 release in vitro and in vivo and prevented entry into the translation-like quality control cycle. Phosphomimetic Ltv1 variants rescued viability after Hrr25 depletion. Ltv1 knockdown in human breast cancer cells impaired apoptosis induced by CK1δ/ε inhibitors, establishing that the antiproliferative activity of these inhibitors is due at least in part to disruption of ribosome assembly. In vitro phosphorylation assay, non-phosphorylatable and phosphomimetic mutants, genetic rescue, siRNA knockdown in human cancer cells, cell viability assay The Journal of cell biology High 25778921
2015 Drosophila LTV1 interacts with ribosomal protein S3 and co-purifies with free 40S ribosome subunits. LTV1 is required for 40S ribosome subunit synthesis and pre-rRNA processing. dMyc directly regulates LTV1 transcription and requires LTV1 to stimulate ribosome biogenesis; loss of LTV1 blocks dMyc-induced cell growth and endoreplication. Co-immunoprecipitation, sucrose gradient fractionation, pre-rRNA processing assay, dMyc ChIP/transcriptional reporter, genetic epistasis (loss-of-function) The Journal of biological chemistry Medium 25858587
2018 Ltv1 facilitates the incorporation of Rps3, Rps10, and Asc1/RACK1 into the small ribosomal subunit head, as shown by structure probing and biochemistry. Ribosomes from Ltv1-deficient yeast have substoichiometric amounts of Rps10 and Asc1 and show defects in translational fidelity and ribosome-mediated RNA quality control. Breast cancer cells have reduced LTV1 levels and produce ribosomes lacking RPS3, RPS10, and RACK1, connecting the chaperone mechanism to cancer cell ribosome diversity. Yeast genetics (deletion), mass spectrometry (quantitative ribosome composition), rRNA structure probing, translational fidelity assay, comparative analysis of human cancer cell lines The Journal of cell biology High 30348748
2022 A homozygous missense variant (c.503A>G, p.Asn168Ser) in LTV1 creates a new donor splice site, causing aberrant splicing and a premature termination codon in exon 6, as confirmed by minigene splicing assay in HEK293T cells and patient skin sample. This loss-of-function variant is linked to the LIPHAK ribosomopathy syndrome, establishing LTV1 as a disease gene in humans. Whole-genome sequencing, homozygosity mapping, minigene splicing assay (HEK293T and patient tissue) Human molecular genetics Medium 34999892
2023 Ltv1 directly binds 5 out of 15 ribosomal proteins in the small subunit head and indirectly affects 4 additional RPs via conformational transitions it regulates in the nascent subunit. Ltv1 aids recruitment of some RPs via direct protein-protein interactions while simultaneously delaying the recruitment of other RPs, thereby controlling hierarchical RP assembly. Delayed RP binding also delays acquisition of RNA structure stabilized by those RPs. Ltv1 directly chaperones folding of the three-helix junction j34-35-38 in rRNA. The LIPHAK disease-associated mutation causes global defects in head assembly consistent with these roles. Yeast genetics, mass spectrometry, DMS chemical probing (rRNA structure), biochemical interaction assays, disease-mutant analysis PLoS genetics High 37910572

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Ltv1 is required for efficient nuclear export of the ribosomal small subunit in Saccharomyces cerevisiae. Genetics 73 16888326
2015 Hrr25/CK1δ-directed release of Ltv1 from pre-40S ribosomes is necessary for ribosome assembly and cell growth. The Journal of cell biology 68 25778921
2004 Genetic and biochemical interactions among Yar1, Ltv1 and Rps3 define novel links between environmental stress and ribosome biogenesis in Saccharomyces cerevisiae. Genetics 50 15611164
2018 Ribosome biogenesis factor Ltv1 chaperones the assembly of the small subunit head. The Journal of cell biology 34 30348748
2010 Dominant mutations in the late 40S biogenesis factor Ltv1 affect cytoplasmic maturation of the small ribosomal subunit in Saccharomyces cerevisiae. Genetics 26 20215468
2014 Genetic analysis of the ribosome biogenesis factor Ltv1 of Saccharomyces cerevisiae. Genetics 19 25213169
2015 Drosophila Low Temperature Viability Protein 1 (LTV1) Is Required for Ribosome Biogenesis and Cell Growth Downstream of Drosophila Myc (dMyc). The Journal of biological chemistry 8 25858587
2021 The Ribosome Biogenesis Factor Ltv1 Is Essential for Digestive Organ Development and Definitive Hematopoiesis in Zebrafish. Frontiers in cell and developmental biology 6 34692673
2023 A disease associated mutant reveals how Ltv1 orchestrates RP assembly and rRNA folding of the small ribosomal subunit head. PLoS genetics 5 37910572
2022 Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder. Human molecular genetics 5 34999892
2023 A disease associated mutant reveals how Ltv1 orchestrates RP assembly and rRNA folding of the small ribosomal subunit head. bioRxiv : the preprint server for biology 0 37503067
2015 Location is everything: an educational primer for use with "genetic analysis of the ribosome biogenesis factor Ltv1 of Saccharomyces cerevisiae". Genetics 0 25657348

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