Affinage

GNL3L

Guanine nucleotide-binding protein-like 3-like protein · UniProt Q9NVN8

Length
582 aa
Mass
65.6 kDa
Annotated
2026-06-10
17 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GNL3L is a nucleolar GTP-binding protein that retains the ancestral function of ribosome biogenesis while also serving as a regulator of cell cycle progression and tumor cell survival (PMID:24610951, PMID:41755636). It associates with human pre-60S ribosomal complexes and contacts pre-rRNAs at defined sites, where its GTP binding and hydrolysis drive distinct steps of pre-rRNA processing; GTPase-inactive GNL3L accumulates on pre-60S particles with proximal assembly factors, and loss of GNL3L impairs 60S rRNA synthesis, protein synthesis, and proliferation (PMID:41755636). This processing role is conserved, as GNL3L rescues pre-rRNA processing, ribosomal protein export, and growth defects of yeast lacking its ortholog Grn1p (PMID:16251348). Nucleolar targeting depends on a lysine-rich nucleolar localization signal that binds importin-β together with GTP-dependent nucleolar retention conferred by its circularly permuted G-domain (PMID:17034816), while a CRM1-dependent nuclear export signal in its C-terminus drives nucleo-cytoplasmic shuttling, with nuclear retention promoting S-phase progression through Rb hyperphosphorylation and upregulation of E2F1 and cyclins (PMID:26274615). Beyond ribosome synthesis, GNL3L acts in cell cycle control by binding and stabilizing TRF1 — blocking its FBX4-mediated ubiquitylation to promote the metaphase-to-anaphase transition (PMID:19487455) — and by binding and stabilizing MDM2 to inhibit its ubiquitylation, thereby suppressing p53 transcriptional targets such as Bax, 14-3-3σ, and p21 (PMID:21132010, PMID:40856423). It additionally inhibits ERRγ transcriptional activity by competing for steroid receptor coactivator binding (PMID:17623774), interacts with LDOC1, and activates NF-κB signaling to drive proliferation and invasion in cancer cells (PMID:27764577, PMID:40466800).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 High

    Establishing whether GNL3L functions in ribosome biogenesis answered what cellular process this GTPase serves, anchoring it to nucleolar pre-rRNA maturation.

    Evidence Yeast deletion genetics, heterologous complementation of Δgrn1, rRNA Northern blot, and siRNA in HeLa cells

    PMID:16251348

    Open questions at the time
    • Did not resolve the direct pre-rRNA or pre-ribosome contacts in human cells
    • Mechanistic role of GTP hydrolysis in processing not defined
  2. 2006 High

    Mapping the nucleolar localization signal and GTP-dependent retention explained how GNL3L reaches and is held in its functional compartment.

    Evidence Deletion mutagenesis, importin-β binding assay, GTP depletion, and structural modeling on the Ylqf GTPase

    PMID:17034816

    Open questions at the time
    • Functional consequence of nucleolar retention on substrate processing not directly tested
    • No experimental structure of human GNL3L
  3. 2007 High

    Identifying GNL3L as an ERRγ repressor revealed a nuclear receptor-regulatory role distinct from ribosome synthesis.

    Evidence Co-IP, domain-mapping mutagenesis, reporter assays, and gain/loss-of-function

    PMID:17623774

    Open questions at the time
    • Physiological gene targets of GNL3L-ERRγ repression not defined
    • Relationship between coactivator competition and GTPase activity unknown
  4. 2009 High

    Showing GNL3L stabilizes TRF1 by blocking FBX4-mediated ubiquitylation connected it to telomere dynamics and mitotic progression.

    Evidence Reciprocal Co-IP, ubiquitylation assays, siRNA depletion, and cell cycle analysis

    PMID:19487455

    Open questions at the time
    • Whether GNL3L-FBX4 competition is direct or scaffolded not resolved
    • Link between TRF1 stabilization and ribosome biogenesis role not addressed
  5. 2010 High

    Demonstrating constitutive MDM2 stabilization placed GNL3L upstream of the p53 transcriptional program independent of p53 stability.

    Evidence Reciprocal Co-IP, ubiquitylation assays, and qRT-PCR/western blot of p53 targets in isogenic p53-WT vs p53-null HCT116 cells

    PMID:21132010

    Open questions at the time
    • Mechanism by which GNL3L blocks MDM2 self-ubiquitylation not defined
    • Whether nucleolar vs nucleoplasmic GNL3L mediates this not separated
  6. 2014 High

    Distinguishing GNL3L's ribosome-production role from its paralog nucleostemin's genome-protective role clarified functional divergence within the family.

    Evidence siRNA knockdown in breast carcinoma cells with ribosome production, rRNA synthesis, and DNA damage assays

    PMID:24610951

    Open questions at the time
    • Molecular step in ribosome production blocked by GNL3L loss not pinpointed in this study
  7. 2015 Medium

    Defining a CRM1-dependent export signal explained how GNL3L shuttling controls S-phase entry.

    Evidence Leptomycin B treatment, point mutagenesis, CRM1 Co-IP, and BrdU/cell cycle analysis

    PMID:26274615

    Open questions at the time
    • Direct cytoplasmic function of exported GNL3L not identified
    • How nuclear retention mechanistically drives Rb phosphorylation unresolved
  8. 2016 Medium

    Identifying LDOC1 as a destabilizing partner and linking GNL3L to NF-κB/p65 connected it to anti-apoptotic and proliferative signaling.

    Evidence Co-IP, ectopic expression/knockdown, NF-κB reporter assay, TNF-α stimulation, and p65 knockdown

    PMID:27764577

    Open questions at the time
    • Mechanism by which LDOC1 destabilizes GNL3L not defined
    • How GNL3L modulates p65 expression mechanistically unknown
  9. 2023 Medium

    Linking GNL3L to AMPK-dependent autophagy and to ATM/p53 stress signaling extended its role to cellular stress responses in cancer and epithelial models.

    Evidence siRNA/overexpression with AMPK agonist/inhibitor epistasis in esophageal cancer; and siRNA in cigarette-smoke COPD models with pathway western blots

    PMID:38022822 PMID:38148364

    Open questions at the time
    • Direct molecular link between GNL3L and AMPK or ATM not established
    • COPD findings rest on western-blot pathway inference without interaction assay
  10. 2025 Medium

    Epistatic rescue confirmed GNL3L drives cancer malignancy through the MDM2-p53-p21 axis and through NF-κB-Slug-MMP effectors.

    Evidence Co-IP, MDM2 and MMP2/MMP9/Slug overexpression/knockdown rescue, invasion assays, and nude mouse xenografts in ESCC and lung cancer cells

    PMID:40466800 PMID:40856423

    Open questions at the time
    • Whether MDM2 and NF-κB pathways are independent or convergent GNL3L outputs unresolved
    • Single-lab studies without reciprocal cross-validation
  11. 2026 High

    Direct pre-60S association and RNA contact mapping established the GTPase-dependent biochemical mechanism of GNL3L in 60S ribosome maturation.

    Evidence Pre-ribosome co-purification, pre-rRNA contact mapping, GTPase-inactive mutant expression, and ribosome profiling

    PMID:41755636

    Open questions at the time
    • Order of GTPase action relative to other assembly factors not fully ordered
    • No high-resolution structure of GNL3L on the pre-60S particle

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GNL3L's conserved nucleolar ribosome-biogenesis function is mechanistically coordinated with its nucleoplasmic roles in TRF1/MDM2 stabilization and NF-κB signaling remains unresolved.
  • Whether ribosome-biogenesis and protein-stabilization activities are spatially or functionally separable is unknown
  • No unified model linking GTPase activity to the non-ribosomal partner interactions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0003924 GTPase activity 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1
Localization
GO:0005654 nucleoplasm 3 GO:0005730 nucleolus 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-9612973 Autophagy 1
Partners
CRM1ESRRGFBX4LDOC1MDM2RELATRF1
Complex memberships
pre-60S ribosomal particle

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 GNL3L binds TRF1 in the nucleoplasm, promotes TRF1 homodimerization and telomeric association, prevents PML body recruitment of telomere-bound TRF1, and stabilizes TRF1 protein by inhibiting its ubiquitylation and binding to FBX4 (an E3 ubiquitin ligase for TRF1). This TRF1-stabilizing activity mediates the mitotic increase of TRF1 and promotes the metaphase-to-anaphase transition. Co-immunoprecipitation, ubiquitylation assays, loss-of-function (siRNA/depletion), cell cycle analysis, in vivo interaction studies The Journal of cell biology High 19487455
2010 GNL3L binds MDM2 in the nucleoplasm and stabilizes MDM2 protein by inhibiting its ubiquitylation. GNL3L depletion triggers G2/M arrest in p53-wild-type cells more than p53-null cells and upregulates p53 targets (Bax, 14-3-3σ, p21) without affecting p53 ubiquitylation or stability, placing GNL3L as a constitutive MDM2 stabilizer upstream of p53 transcriptional targets. Co-immunoprecipitation, ubiquitylation assays, siRNA knockdown, cell cycle analysis, qRT-PCR/western blot of p53 targets in p53-WT vs p53-null HCT116 cells Oncogene High 21132010
2014 GNL3L depletion markedly impairs ribosome production without inducing appreciable DNA damage, establishing that GNL3L retains the ancestral invertebrate GNL3 function in ribosome biosynthesis, while its paralog nucleostemin has diverged to a genome-protective role. siRNA knockdown in human breast carcinoma cells, ribosome production assays, DNA damage assays (S-phase), rRNA synthesis measurement Journal of cell science High 24610951
2007 GNL3L binds ERRγ through its intermediate domain (interacting with the AF2 domain of ERRγ) in the nucleoplasm and inhibits ERRγ transcriptional activity by competing for steroid receptor coactivator (SRC) binding, reducing SRC-mediated transcriptional coactivation of ERRγ. Co-immunoprecipitation, deletion mutagenesis, cell-based reporter assays, gain- and loss-of-function experiments, co-localization Journal of cell science High 17623774
2006 GNL3L is transported to the nucleolus via a novel lysine-rich nucleolar localization signal (NoLS) within residues 1–50 that interacts with importin-β. GTP binding (via circularly permuted G-motifs in G5-G4-G1-G2-G3 pattern) is also required for nucleolar retention; G-domain mutations abrogate nucleolar retention even when NoLS is functional, and depletion of intracellular GTP blocks nucleolar accumulation. Deletion mutagenesis, heterologous targeting assays, importin-β binding assay, GTP depletion, 3D structural modeling based on Ylqf GTPase crystal structure Journal of molecular biology High 17034816
2005 GNL3L (and its fission yeast ortholog Grn1p) is required for processing of nucleolar pre-rRNA; deletion of Grn1p causes accumulation of 35S pre-rRNA, failure to export ribosomal protein Rpl25a from the nucleolus, and severe growth defect. Heterologous expression of GNL3L in Δgrn1 yeast rescues pre-rRNA processing, Rpl25a export, and cell growth. Yeast deletion genetics, heterologous complementation, rRNA Northern blot, fluorescence microscopy (Rpl25a localization), siRNA knockdown in HeLa cells Molecular biology of the cell High 16251348
2015 GNL3L is a nucleo-cytoplasmic shuttling protein exported from the nucleus via a CRM1-dependent nuclear export signal (NES) located in the C-terminal domain (aa 501–582); hydrophobic residues M567, L570, and L572 are required for export. Nuclear (export-defective) GNL3L promotes S-phase progression by increasing Rb hyperphosphorylation at Ser780 and upregulating E2F1, cyclins A2 and E1. Leptomycin B treatment, deletion/point mutagenesis, Co-IP with CRM1, cell cycle analysis, BrdU labeling, western blot PloS one Medium 26274615
2016 LDOC1 is a novel GNL3L-interacting protein; ectopic LDOC1 destabilizes endogenous GNL3L and suppresses GNL3L-induced cell proliferation. GNL3L upregulates NF-κB-dependent transcription by modulating p65 expression; LDOC1 co-expression reverses this. GNL3L also potentiates TNF-α-mediated NF-κB activity, and its anti-apoptotic function requires p65. Co-immunoprecipitation, ectopic expression/knockdown, NF-κB reporter assay, TNF-α stimulation, p65 knockdown, cell proliferation assays Cell cycle (Georgetown, Tex.) Medium 27764577
2023 GNL3L positively regulates autophagy and cell proliferation in esophageal cancer cells via the AMPK signaling pathway; GNL3L overexpression increases autophagic flux and AMPK activity, while GNL3L silencing reduces both. AMPK agonist (AICAR) rescues autophagic flux in GNL3L-silenced cells, and pharmacological/genetic AMPK inhibition attenuates GNL3L-induced autophagy. siRNA knockdown, overexpression, immunoblotting, RT-PCR, AMPK agonist/inhibitor treatment, genetic AMPK deprivation, autophagic flux assays Medical oncology (Northwood, London, England) Medium 38148364
2025 GNL3L interacts with MDM2 in esophageal squamous cell carcinoma (ESCC) cells; GNL3L knockdown decreases MDM2 protein levels and increases p53 and p21. MDM2 overexpression rescues malignant characteristics suppressed by GNL3L knockdown, and MDM2 knockdown inhibits malignancy reversible by GNL3L overexpression, confirming GNL3L acts through MDM2 to regulate the MDM2–p53–p21 axis. Co-immunoprecipitation, siRNA knockdown, MDM2 overexpression/knockdown rescue experiments, western blot, EdU/CCK8 proliferation assays, nude mouse xenograft Cancer medicine Medium 40856423
2026 GNL3L associates with human pre-60S ribosomal complexes and contacts pre-rRNAs at defined binding sites. GNL3L's GTPase activity (GTP binding and hydrolysis) is required for distinct steps of pre-rRNA processing; GTPase-inactive GNL3L accumulates on pre-60S particles together with proximal assembly factors. Loss of GNL3L impairs 60S rRNA synthesis, protein synthesis, and cellular proliferation. Pre-ribosome co-purification/compositional analysis, pre-rRNA processing assays, GTPase-inactive mutant expression, RNA contact site mapping, western blot, ribosome profiling Nucleic acids research High 41755636
2025 GNL3L activates NF-κB signaling and upregulates Slug, MMP2, and MMP9 in lung cancer cells; GNL3L deficiency suppresses proliferation, migration, and invasion, and this suppression is fully rescued by co-overexpression of MMP2+MMP9 or Slug+NF-κB activator, placing GNL3L upstream of NF-κB and these downstream effectors. siRNA knockdown, overexpression, NF-κB activation assays, Slug/MMP2/MMP9 overexpression rescue, wound healing, Transwell invasion, nude mouse xenograft Experimental cell research Medium 40466800
2023 GNL3L knockdown in a COPD model inhibits the ATM/p53 pathway (reduces ATM, p53, and p21 protein levels) and reduces inflammation and oxidative stress, linking GNL3L to ATM/p53 activation in epithelial stress responses. siRNA knockdown in cigarette smoke extract-treated human bronchial epithelial cells and CS/LPS-induced mouse model, western blot, ELISA for inflammatory/oxidative markers International journal of chronic obstructive pulmonary disease Low 38022822

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 GNL3L stabilizes the TRF1 complex and promotes mitotic transition. The Journal of cell biology 46 19487455
2005 The homologous putative GTPases Grn1p from fission yeast and the human GNL3L are required for growth and play a role in processing of nucleolar pre-rRNA. Molecular biology of the cell 42 16251348
2010 GNL3L depletion destabilizes MDM2 and induces p53-dependent G2/M arrest. Oncogene 36 21132010
2014 Nucleostemin and GNL3L exercise distinct functions in genome protection and ribosome synthesis, respectively. Journal of cell science 33 24610951
2016 Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation. Cell cycle (Georgetown, Tex.) 28 27764577
2007 GNL3L inhibits activity of estrogen-related receptor gamma by competing for coactivator binding. Journal of cell science 27 17623774
2020 Chemoresistance-Associated Silencing of miR-4454 Promotes Colorectal Cancer Aggression through the GNL3L and NF-κB Pathway. Cancers 25 32422901
2006 A novel lysine-rich domain and GTP binding motifs regulate the nucleolar retention of human guanine nucleotide binding protein, GNL3L. Journal of molecular biology 21 17034816
2015 GNL3L Is a Nucleo-Cytoplasmic Shuttling Protein: Role in Cell Cycle Regulation. PloS one 19 26274615
2009 Nucleolar modulation of TRF1: a dynamic way to regulate telomere and cell cycle by nucleostemin and GNL3L. Cell cycle (Georgetown, Tex.) 14 19713769
2023 Knockdown of GNL3L Alleviates the Progression of COPD Through Inhibiting the ATM/p53 Pathway. International journal of chronic obstructive pulmonary disease 7 38022822
2023 Calycosin inhibits gemcitabine-resistant lung cancer cells proliferation through modulation of the LDOC1/GNL3L/NFκB. The Chinese journal of physiology 6 37635478
2023 GNL3L promotes autophagy via regulating AMPK signaling in esophageal cancer cells. Medical oncology (Northwood, London, England) 5 38148364
2026 Distinct steps of nuclear maturation of human pre-60S complexes require the activity of GTPases including GNL3L. Nucleic acids research 0 41755636
2025 Role of GNL3L in lung cancer: Mediating proliferation and progression through NF-κB pathway activation and upregulation of Slug, MMP2, and MMP9. Experimental cell research 0 40466800
2025 The GNL3L-MDM2 Interaction Drives Esophageal Squamous Cell Carcinoma Progression. Cancer medicine 0 40856423
2024 Revealing the oncogenic role of elevated GNL3L expression in esophageal squamous cell carcinoma: insights into the STAT3 pathway. Journal of thoracic disease 0 38738247

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