Affinage

GNL3

Guanine nucleotide-binding protein-like 3 · UniProt Q9BVP2

Round 2 corrected
Length
549 aa
Mass
62.0 kDa
Annotated
2026-04-28
130 papers in source corpus 4 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GNL3 (nucleostemin) is a nucleolar GTPase that functions in ribosome biogenesis and stem/progenitor cell proliferation. It contains an N-terminal basic domain that mediates nucleolar localization, RNA binding, association with pre-60S ribosomal particles, and direct interaction with p53 (PMID:12464630, PMID:16803892). Its circularly permuted GTPase domain exhibits potassium-stimulated GTP hydrolysis activity and is required for recruiting the RNA helicase Dbp10 to the peptidyl transferase center during 60S subunit maturation; loss of GNL3 or mutation of its nucleotide-binding site causes 60S biogenesis defects and p53-dependent apoptosis (PMID:26823502, PMID:12464630). GNL3 also regulates neuronal progenitor proliferation and differentiation, and bipolar disorder-associated eQTL variants modulate its expression in human neural progenitor cells (PMID:32826963).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2002 High

    Discovery of nucleostemin established that a nucleolar GTPase controls stem and cancer cell proliferation via p53 interaction, answering whether nucleolar GTP-binding proteins directly link to cell-cycle control.

    Evidence Immunofluorescence, co-IP with p53, siRNA depletion, and GTP-binding domain mutant overexpression in CNS stem cells and cancer lines

    PMID:12464630

    Open questions at the time
    • Enzymatic parameters of GTPase activity not measured
    • No ribosome biogenesis role identified at this stage
    • Mechanism linking p53 interaction to cell-cycle arrest not resolved
  2. 2006 High

    Characterization of the yeast ortholog Nug1 revealed that GNL3-family proteins associate with pre-60S ribosomal particles via their N-terminal RNA-binding domain, establishing a direct function in ribosome biogenesis rather than only p53 signaling.

    Evidence Domain-deletion analysis, in vitro GTPase and RNA-binding assays, fluorescence localization, and genetic interactions with pre-60S factors (Noc2, Noc3, Dbp10) in S. cerevisiae

    PMID:16803892

    Open questions at the time
    • Precise binding site on the pre-ribosome unknown
    • Whether the GTPase cycle is regulated by cofactors not determined
    • Functional significance of intrinsic GTPase activity unclear given its dispensability for growth
  3. 2016 High

    Reconstitution of the Nug1–Dbp10 interaction and mapping of their rRNA crosslink sites to helix H89 demonstrated that GNL3 recruits an RNA helicase to the peptidyl transferase center during 60S maturation, and that potassium ions stimulate its GTPase activity.

    Evidence In vitro GTPase assay with cation titration, in vitro reconstitution of Nug1–Dbp10 complex using Chaetomium thermophilum proteins, in vivo UV crosslinking, and yeast depletion/mutant phenotyping

    PMID:26823502

    Open questions at the time
    • Structural basis of the Nug1–Dbp10 interaction not resolved
    • How GTP hydrolysis cycle couples to Dbp10 recruitment or release is unknown
    • Whether the mammalian GNL3 retains identical ribosomal contacts not tested
  4. 2020 Medium

    Linking bipolar disorder-associated eQTLs to GNL3 expression and showing that GNL3 perturbation disrupts neural progenitor proliferation and differentiation extended its role from general stem cell maintenance to specific neuropsychiatric-relevant neurodevelopment.

    Evidence Dual luciferase reporter, CRISPRi in human neural progenitor cells, siRNA/cDNA perturbation in 2D and 3D forebrain organoid models

    PMID:32826963

    Open questions at the time
    • Molecular pathway downstream of GNL3 in neural progenitors not identified
    • Whether neural phenotypes are p53-dependent or ribosome-biogenesis-dependent not distinguished
    • Causal relationship between GNL3 dosage and bipolar disorder in patients not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how GNL3's ribosome biogenesis function and its p53 interaction are mechanistically coordinated, and whether its GTPase cycle acts as a checkpoint coupling 60S maturation to cell proliferation decisions.
  • No structural model of mammalian GNL3 on the pre-60S particle
  • GTPase-activating or guanine-exchange factors for GNL3 not identified
  • Relative contribution of ribosome biogenesis versus p53 signaling to proliferation phenotypes not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-1640170 Cell Cycle 1
Partners
DBP10NOC2NOC3TP53
Complex memberships
pre-60S ribosomal particle

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Nucleostemin (GNL3) is a novel nucleolar protein preferentially expressed in CNS stem cells, embryonic stem cells, and cancer cell lines. It contains an N-terminal basic domain required for nucleolar localization and two GTP-binding motifs. Depletion or overexpression of nucleostemin reduces cell proliferation; overexpression of GTP-binding mutants lacking the GTP-regulatory domain prevents mitotic entry and causes p53-dependent apoptosis. The N-terminal basic domain mediates direct interaction with p53 and is required for the cell death caused by overexpression. Immunofluorescence localization, loss-of-function (antisense/siRNA depletion), overexpression of wild-type and domain-deletion/point mutants, co-immunoprecipitation with p53, cell-cycle analysis, apoptosis assays in CNS stem cells and cancer lines Genes & development High 12464630
2006 The yeast GNL3 ortholog Nug1 associates with multiple pre-60S ribosomal particles in the nucleolus and nucleoplasm. Its eukaryote-specific N-terminal domain (Nug1-N) is both necessary and sufficient for nucleolar/nuclear targeting and for association with pre-60S particles; Nug1-N exhibits RNA-binding activity. The central circularly permuted GTPase domain has intrinsic GTP hydrolysis activity in vitro but is not essential for cell growth. The conserved C-terminal domain is essential for ribosome biogenesis. Domain-deletion analysis, subcellular localization by fluorescence microscopy, RNA-binding assays, in vitro GTPase activity assay, genetic complementation, allele-specific genetic interactions with pre-60S factors Noc2, Noc3, and Dbp10 The Journal of biological chemistry High 16803892
2016 Yeast Nug1 (GNL3 ortholog) exhibits low intrinsic GTPase activity that is specifically stimulated by potassium ions, establishing it as a cation-dependent GTPase. Nug1 physically interacts with the RNA helicase Dbp10, and this interaction can be reconstituted in vitro using Chaetomium thermophilum orthologs. In vivo rRNA-protein crosslinking shows Nug1 and Dbp10 bind at proximal and partially overlapping sites on pre-60S particles, most prominently at helix H89 of the peptidyl transferase center (PTC). Depletion of Nug1 or expression of a nucleotide-binding mutant causes 60S biogenesis defects and loss of Dbp10 from early pre-60S particles. In vitro GTPase enzymatic assay with cation titration, in vitro reconstitution of Nug1-Dbp10 interaction, in vivo rRNA-protein UV crosslinking, yeast depletion and nucleotide-binding mutant expression, sucrose gradient sedimentation Nucleic acids research High 26823502
2020 BD-associated eQTL SNPs (rs10865973, rs12635140, rs4687644) regulate GNL3 expression in human neural progenitor cells, as demonstrated by dual luciferase reporter assay and CRISPR interference. GNL3 knockdown and overexpression cause aberrant neuronal proliferation and differentiation in 2D human neural cell cultures and 3D forebrain organoid models, placing GNL3 in a neuronal proliferation/differentiation regulatory pathway. Dual luciferase reporter assay, CRISPR interference (CRISPRi) in human neural progenitor cells, siRNA knockdown and cDNA overexpression in 2D neural cultures and 3D forebrain organoids, proliferation and differentiation assays Molecular psychiatry Medium 32826963

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Biological insights from 108 schizophrenia-associated genetic loci. Nature 5878 25056061
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2013 Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nature genetics 1192 23974872
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2011 Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature genetics 1068 21926972
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2010 A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Progress in neuro-psychopharmacology & biological psychiatry 836 20471444
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2002 Directed proteomic analysis of the human nucleolus. Current biology : CB 780 11790298
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 Selective silencing of foreign DNA with low GC content by the H-NS protein in Salmonella. Science (New York, N.Y.) 589 16763111
2005 Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell 544 16213212
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. Journal of proteome research 422 20020773
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2012 Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. PLoS genetics 400 22479202
2002 Functional proteomic analysis of human nucleolus. Molecular biology of the cell 391 12429849
2002 A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes & development 377 12464630
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
1975 Both NS and L proteins are required for in vitro RNA synthesis by vesicular stomatitis virus. Journal of virology 315 167189
2006 Bacterial chromatin organization by H-NS protein unravelled using dual DNA manipulation. Nature 285 17108966
2009 Structure and functionality in flavivirus NS-proteins: perspectives for drug design. Antiviral research 255 19945487
2000 H-NS mediated compaction of DNA visualised by atomic force microscopy. Nucleic acids research 232 10982869
2010 Identification and characterization of E. coli CRISPR-cas promoters and their silencing by H-NS. Molecular microbiology 222 20132443
2006 Adherent neural stem (NS) cells from fetal and adult forebrain. Cerebral cortex (New York, N.Y. : 1991) 206 16766697
2010 A divalent switch drives H-NS/DNA-binding conformations between stiffening and bridging modes. Genes & development 202 20159954
1994 The chromatin-associated protein H-NS alters DNA topology in vitro. The EMBO journal 188 8306968
2010 H-NS forms a superhelical protein scaffold for DNA condensation. Proceedings of the National Academy of Sciences of the United States of America 169 20798056
2007 An H-NS-like stealth protein aids horizontal DNA transmission in bacteria. Science (New York, N.Y.) 169 17218529
2008 New insights into transcriptional regulation by H-NS. Current opinion in microbiology 166 18387844
1993 The NS 3 nonstructural protein of flaviviruses contains an RNA triphosphatase activity. Virology 163 8212562
1994 The H-NS protein is involved in the biogenesis of flagella in Escherichia coli. Journal of bacteriology 160 8071234
2014 Widespread suppression of intragenic transcription initiation by H-NS. Genes & development 126 24449106
1999 Domain organization and oligomerization among H-NS-like nucleoid-associated proteins in bacteria. Trends in microbiology 126 10203842
2003 The H-NS dimerization domain defines a new fold contributing to DNA recognition. Nature structural biology 120 12592399
1994 The chromatin-associated protein H-NS. Biochimie 106 7748941
2000 Oligomerization of the chromatin-structuring protein H-NS. Molecular microbiology 102 10844682
2017 Mechanism of environmentally driven conformational changes that modulate H-NS DNA-bridging activity. eLife 99 28949292
2008 Selective repression by Fis and H-NS at the Escherichia coli dps promoter. Molecular microbiology 97 18452510
1990 NS-1 and NS-2 proteins may act synergistically in the cytopathogenicity of parvovirus MVMp. Virology 96 2137660
2001 A molecular mechanism for the repression of transcription by the H-NS protein. Molecular microbiology 94 11886561
1987 Localization and immunological characterization of antigenic domains of the rabies virus internal N and NS proteins. Virus research 93 2445121
2007 LeuO antagonizes H-NS and StpA-dependent repression in Salmonella enterica ompS1. Molecular microbiology 90 17908208
2013 H-NS plays a role in expression of Acinetobacter baumannii virulence features. Infection and immunity 88 23649094
2010 Salmonella enterica response regulator SsrB relieves H-NS silencing by displacing H-NS bound in polymerization mode and directly activates transcription. The Journal of biological chemistry 88 21059643
2001 Structural basis for preferential binding of H-NS to curved DNA. Biochimie 88 11278073
1978 Effects of phosphorylation and pH on the association of NS protein with vesicular stomatitis virus cores. Journal of virology 88 29135
2016 Structure and function of bacterial H-NS protein. Biochemical Society transactions 87 27913665
2003 Reovirus sigma NS and mu NS proteins form cytoplasmic inclusion structures in the absence of viral infection. Journal of virology 87 12719587
1996 Antagonistic involvement of FIS and H-NS proteins in the transcriptional control of hns expression. Molecular microbiology 85 8830277
2012 Nucleoprotein filament formation is the structural basis for bacterial protein H-NS gene silencing. Scientific reports 83 22798986
2014 Silencing by H-NS potentiated the evolution of Salmonella. PLoS pathogens 79 25375226
1989 Vesicular stomatitis virus RNA replication: a role for the NS protein. The Journal of general virology 78 2552006
2002 The bacterial regulatory protein H-NS--a versatile modulator of nucleic acid structures. Biological chemistry 76 12222684
1985 In vitro phosphorylation of NS protein by the L protein of vesicular stomatitis virus. The Journal of general virology 75 2987394
2021 Stereochemical expression of ns2 electron pairs in metal halide perovskites. Nature reviews. Chemistry 74 37117392
2003 Reovirus sigma NS protein localizes to inclusions through an association requiring the mu NS amino terminus. Journal of virology 69 12663763
1995 Antibodies to parvovirus B19 NS-1 protein in infected individuals. The Journal of general virology 66 7534811
2010 Peptide and protein thioester synthesis via N-->S acyl transfer. Organic & biomolecular chemistry 62 20401371
2004 Regulation of Escherichia coli hemolysin E expression by H-NS and Salmonella SlyA. Journal of bacteriology 61 14996792
2012 Basis for the essentiality of H-NS family members in Pseudomonas aeruginosa. Journal of bacteriology 60 22821971
2005 A truncated H-NS-like protein from enteropathogenic Escherichia coli acts as an H-NS antagonist. Molecular microbiology 60 15661006
1998 H-NS and StpA proteins stimulate expression of the maltose regulon in Escherichia coli. Journal of bacteriology 60 9829919
2015 H-NS and RNA polymerase: a love-hate relationship? Current opinion in microbiology 59 25638302
1998 A role for H-NS in the regulation of the virF gene of Shigella and enteroinvasive Escherichia coli. Research in microbiology 59 9766205
2021 A Look into Bunyavirales Genomes: Functions of Non-Structural (NS) Proteins. Viruses 56 33670641
1997 DNA binding is not sufficient for H-NS-mediated repression of proU expression. The Journal of biological chemistry 56 9115277
2010 Decrypting the H-NS-dependent regulatory cascade of acid stress resistance in Escherichia coli. BMC microbiology 54 21034467
2019 H-NS uses an autoinhibitory conformational switch for environment-controlled gene silencing. Nucleic acids research 52 30597093
2006 The NUG1 GTPase reveals and N-terminal RNA-binding domain that is essential for association with 60 S pre-ribosomal particles. The Journal of biological chemistry 51 16803892
2020 Sulfonamides incorporating ketene N,S-acetal bioisosteres as potent carbonic anhydrase and acetylcholinesterase inhibitors. Archiv der Pharmazie 50 32285537
2005 SAT: a late NS protein of porcine parvovirus. Journal of virology 50 16189014
1986 Phosphoprotein NS of vesicular stomatitis virus: phosphorylated states and transcriptional activities of intracellular and virion forms. Virology 50 3020780
2005 Nature and mechanism of the in vivo oligomerization of nucleoid protein H-NS. The EMBO journal 48 16052211
2010 H-NS binding and repression of the ctx promoter in Vibrio cholerae. Journal of bacteriology 43 21169492
2016 ToxR Antagonizes H-NS Regulation of Horizontally Acquired Genes to Drive Host Colonization. PLoS pathogens 39 27070545
2012 H-NS regulation of IraD and IraM antiadaptors for control of RpoS degradation. Journal of bacteriology 38 22408168
1996 H-NS regulates OmpF expression through micF antisense RNA in Escherichia coli. Journal of bacteriology 38 8655567
2001 Sequence diversity of NS(M) movement protein of tospoviruses. Archives of virology 36 11556705
1997 Variability of the NS(S) protein among Rift Valley fever virus isolates. The Journal of general virology 36 9367372
2016 The K⁺-dependent GTPase Nug1 is implicated in the association of the helicase Dbp10 to the immature peptidyl transferase centre during ribosome maturation. Nucleic acids research 35 26823502
2009 Investigation of the self-association and hetero-association interactions of H-NS and StpA from Enterobacteria. Molecular microbiology 35 19508284
1984 Characterization of the phosphorylated small enzyme subunit, NS, of the vesicular stomatitis virus RNA polymerase. The Journal of biological chemistry 35 6092379
2014 Exploring the interaction of N/S compounds with a dicopper center: tyrosinase inhibition and model studies. Inorganic chemistry 34 25415587
2000 Effects of local transcription and H-NS on inversion of the fim switch of Escherichia coli. Molecular microbiology 34 10792731
2012 The N's and O's of Drosophila glycoprotein glycobiology. Glycoconjugate journal 33 22936173
2005 LRP and H-NS--cooperative partners for transcription regulation at Escherichia coli rRNA promoters. Molecular microbiology 32 16238633
2016 The Nucleoid Binding Protein H-NS Biases Genome-Wide Transposon Insertion Landscapes. mBio 31 27578758
1984 Protein kinase activity associated with immunoprecipitates of the vesicular stomatitis virus phosphoprotein NS. Virology 31 6322412
2018 A single molecule analysis of H-NS uncouples DNA binding affinity from DNA specificity. Nucleic acids research 29 30239908
2013 Effect of H-NS on the elongation and compaction of single DNA molecules in a nanospace. Soft matter 29 26029766
2023 c-di-GMP inhibits the DNA binding activity of H-NS in Salmonella. Nature communications 28 37980414
2019 Predicting the mechanism and rate of H-NS binding to AT-rich DNA. PLoS computational biology 28 30845209
2015 Producing human ceramide-NS by metabolic engineering using yeast Saccharomyces cerevisiae. Scientific reports 28 26573460
1997 Characterization of BpH3, an H-NS-like protein in Bordetella pertussis. Molecular microbiology 28 9194708
1989 Characterization of the structural genes for the DNA-binding protein H-NS in Enterobacteriaceae. FEBS letters 26 2494066
2012 Gene silencing by H-NS from distal DNA site. Molecular microbiology 25 22924981
2018 Interference of transcription across H-NS binding sites and repression by H-NS. Molecular microbiology 23 29424946
2013 A model of H-NS mediated compaction of bacterial DNA. Biophysical journal 23 23561538
2005 Epitope mapping and functional analysis of sigma A and sigma NS proteins of avian reovirus. Virology 23 15680423
2024 H-NS is a bacterial transposon capture protein. Nature communications 22 39164300
2022 The B. subtilis Rok protein is an atypical H-NS-like protein irresponsive to physico-chemical cues. Nucleic acids research 22 36408910
2016 H-NS, Its Family Members and Their Regulation of Virulence Genes in Shigella Species. Genes 22 27916940
2010 Global regulator H-NS and lipoprotein NlpI influence production of extracellular DNA in Escherichia coli. Biochemical and biophysical research communications 22 20833130
2021 Xenogeneic silencing relies on temperature-dependent phosphorylation of the host H-NS protein in Shewanella. Nucleic acids research 20 33693785
2020 Integrative analyses prioritize GNL3 as a risk gene for bipolar disorder. Molecular psychiatry 20 32826963
2019 NusG prevents transcriptional invasion of H-NS-silenced genes. PLoS genetics 20 31589608
2014 The Intimin-Like Protein FdeC Is Regulated by H-NS and Temperature in Enterohemorrhagic Escherichia coli. Applied and environmental microbiology 20 25239893
2013 Characterization of the ospZ promoter in Shigella flexneri and its regulation by VirB and H-NS. Journal of bacteriology 20 23543709
2004 Protective role for H-NS protein in IS1 transposition. Journal of bacteriology 19 15028694
2003 H-NS and Lrp serve as positive modulators of traJ expression from the Escherichia coli plasmid pRK100. Molecular genetics and genomics : MGG 19 12942368
1991 Two distinct protein kinase activities in vesicular stomatitis virions phosphorylate the NS transcription factor. Virology 19 1651598
2017 Serotype-specific interactions among functional domains of dengue virus 2 nonstructural proteins (NS) 5 and NS3 are crucial for viral RNA replication. The Journal of biological chemistry 18 28396347
2003 Protein stability and plasticity of the hydrophobic cavity in wheat ns-LTP. Journal of biomolecular structure & dynamics 18 12854956
1997 H-NS protein represses transcription of the lux systems of Vibrio fischeri and other luminous bacteria cloned into Escherichia coli. Current microbiology 18 9353217
2019 H-NS is the major repressor of Salmonella Typhimurium Pef fimbriae expression. Virulence 17 31661351
2012 An influenza reassortant with polymerase of pH1N1 and NS gene of H3N2 influenza A virus is attenuated in vivo. The Journal of general virology 17 22323532