Affinage

ZNHIT2

Zinc finger HIT domain-containing protein 2 · UniProt Q9UHR6

Length
403 aa
Mass
42.9 kDa
Annotated
2026-06-11
97 papers in source corpus 3 papers cited in narrative 3 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNHIT2 is a zinc-finger HIT domain protein that acts as a bridging factor coupling the R2TP/Prefoldin-like (R2TP/PFDL) cochaperone machinery to U5 snRNP assembly (PMID:28561026). Its HIT domain adopts a novel treble-clef-like zinc-binding fold that coordinates two zinc ions tetrahedrally through an interleaved CCCC-CCHC cross-brace motif, structurally related to but distinct from B-box, RING, and PHD domains (PMID:17656577). Through this domain ZNHIT2 binds directly to the AAA+ ATPase RUVBL2, and disruption of either ZNHIT2 or RUVBL2 alters the protein composition of the U5 snRNP, establishing ZNHIT2 as a promoter of U5 snRNP biogenesis (PMID:28561026). In vivo, loss of Znhit2 in mouse embryos abolishes nuclear localization of the U5 component EFTUD2, producing a global splicing deficiency, disrupted pluripotency marker expression, and peri-implantation lethality, a phenotype mechanistically distinct from Znhit1 loss (PMID:39194072).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2007 High

    Before any functional assignment, the structural basis of the ZNHIT2 zinc-finger HIT domain was unknown; solving it defined a distinct zinc-coordination architecture that would later rationalize its protein-binding role.

    Evidence NMR solution structure of the human ZNHIT2 (FON) HIT domain with quantitative NOE restraints

    PMID:17656577

    Open questions at the time
    • Structure covers only the isolated HIT domain, not the full-length protein
    • Does not identify any binding partner or functional interface
    • No link to spliceosome biology established at this stage
  2. 2017 High

    It was unclear how the R2TP/PFDL cochaperone complex connects to spliceosomal snRNPs; ZNHIT2 was identified as the bridging adaptor that binds RUVBL2 and promotes U5 snRNP assembly.

    Evidence Reciprocal AP-MS across multiple targets plus siRNA knockdown of ZNHIT2 and RUVBL2 with analysis of U5 snRNP composition in human cells

    PMID:28561026

    Open questions at the time
    • Stoichiometry and exact assembly intermediate captured by ZNHIT2 not resolved
    • Whether ZNHIT2 acts catalytically or as a one-time scaffold unclear
    • In vivo physiological consequence of disrupting the bridge not tested here
  3. 2024 High

    The organismal requirement for ZNHIT2 was unknown; knockout showed it is essential for U5 spliceosome integrity in vivo, with loss abolishing nuclear EFTUD2 and causing peri-implantation lethality.

    Evidence Znhit2 knockout mouse genetics with EFTUD2 immunofluorescence and pluripotency marker quantification in blastocysts

    PMID:39194072

    Open questions at the time
    • Direct splicing targets affected genome-wide not enumerated
    • Mechanism by which EFTUD2 fails to enter the nucleus not resolved at molecular level
    • Relationship between the in vitro RUVBL2-bridging role and the in vivo EFTUD2 phenotype not directly connected

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZNHIT2-directed U5 snRNP assembly is coupled to ATP-dependent RUVBL1/2 remodeling and how the chaperone hands off mature components remains unresolved.
  • No reconstituted assembly assay defining the ZNHIT2-dependent step
  • Structure of ZNHIT2 bound to RUVBL2 or U5 components not determined
  • Regulation of ZNHIT2 activity across cell types and conditions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 2
Partners
EFTUD2RUVBL2
Complex memberships
R2TP/Prefoldin-like cochaperone complexU5 snRNP

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 ZNHIT2 mediates the interaction between the R2TP/Prefoldin-like (R2TP/PFDL) cochaperone complex and the U5 small nuclear ribonucleoprotein (snRNP). Affinity purification coupled to mass spectrometry showed that R2TP/PFDL associates with the U5 snRNP mostly through ZNHIT2. The zinc-finger HIT domain of ZNHIT2 directly binds RUVBL2. Disruption of ZNHIT2 or RUVBL2 expression impacts the protein composition of the U5 snRNP, indicating a role for these proteins in promoting U5 snRNP assembly. Multiple target affinity purification coupled to mass spectrometry (AP-MS); siRNA knockdown of ZNHIT2 and RUVBL2 followed by analysis of U5 snRNP protein composition Nature Communications High 28561026
2007 The zinc-finger HIT domain of human ZNHIT2 (protein FON) adopts a novel zinc-binding fold consisting of two consecutive antiparallel beta-sheets and two short C-terminal helices, coordinating two zinc ions tetrahedrally via a CCCC-CCHC motif in an interleaved cross-brace manner. The tertiary structure resembles the B-box, RING finger, and PHD domain family (treble clef superfamily) but is distinct from all of them. NMR solution structure determination using 3D NOESY spectra (567 upper distance limits); backbone RMSD 0.19 Å for structured residues 12–48 Protein Science High 17656577
2024 Knockout of Znhit2 in mouse embryos causes embryonic lethality at peri-implantation stages. Znhit2 mutant embryos display a complete lack of nuclear EFTUD2 (a key U5 spliceosome component), indicating a global splicing deficiency. This is mechanistically distinct from Znhit1 loss, which impairs H2A.Z incorporation at gene promoters. Znhit2 mutant embryos also show reduced SOX2-positive inner cell mass cells, absent Fgf4 expression, and aberrant NANOG/SOX17 expression. Knockout mouse genetics; immunofluorescence for EFTUD2 nuclear localization; quantification of pluripotency markers (SOX2, NANOG, SOX17) and Fgf4 expression in mutant blastocysts Biology of Reproduction High 39194072

Source papers

Stage 0 corpus · 97 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. Future oncology (London, England) 178 34278827
2003 Exosomes bearing HLA-G are released by melanoma cells. Human immunology 107 14602237
2017 R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein. Nature communications 96 28561026
2005 HLA-G gene activation in tumor cells involves cis-acting epigenetic changes. International journal of cancer 55 15514928
2019 Comparative Transcriptome Analysis Reveals the Biocontrol Mechanism of Bacillus velezensis F21 Against Fusarium Wilt on Watermelon. Frontiers in microbiology 54 31001229
2005 Craniofacial and axial skeletal defects induced by the fungicide triadimefon in the mouse. Birth defects research. Part B, Developmental and reproductive toxicology 54 15834900
2006 The Toll immune-regulated Drosophila protein Fondue is involved in hemolymph clotting and puparium formation. Developmental biology 48 16690050
2021 INSIGHT 2: a phase II study of tepotinib plus osimertinib in MET-amplified NSCLC and first-line osimertinib resistance. Future oncology (London, England) 47 34918545
2017 Haplotypes of the HLA-G 3' Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially. PloS one 42 28045999
2020 CRISPR/Cas9-mediated mutagenesis of Clpsk1 in watermelon to confer resistance to Fusarium oxysporum f.sp. niveum. Plant cell reports 40 32152696
2016 The FonSIX6 gene acts as an avirulence effector in the Fusarium oxysporum f. sp. niveum - watermelon pathosystem. Scientific reports 38 27320044
2006 Increase in HLA-G1 proteolytic shedding by tumor cells: a regulatory pathway controlled by NF-kappaB inducers. Cellular and molecular life sciences : CMLS 37 17072500
2003 Signalling pathways regulating the tight junction permeability in the blood-brain barrier. Cellular and molecular biology (Noisy-le-Grand, France) 37 12839334
2010 Development of the molecular methods for rapid detection and differentiation of Fusarium oxysporum and F. oxysporum f. sp. niveum in Taiwan. New biotechnology 35 20471505
2022 Bio-Functionalized Manganese Nanoparticles Suppress Fusarium Wilt in Watermelon (Citrullus lanatus L.) by Infection Disruption, Host Defense Response Potentiation, and Soil Microbial Community Modulation. Small (Weinheim an der Bergstrasse, Germany) 34 36382544
2018 Wheat Intercropping Enhances the Resistance of Watermelon to Fusarium Wilt. Frontiers in plant science 34 29887873
2016 The components of rice and watermelon root exudates and their effects on pathogenic fungus and watermelon defense. Plant signaling & behavior 32 27217091
1997 Construction of a 1.2-Mb sequence-ready contig of chromosome 11q13 encompassing the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Genomics 28 9286704
2006 Triadimefon causes branchial arch malformations in Xenopus laevis embryos. Environmental science and pollution research international 27 16910123
2008 Molecular mechanism of teratogenic effects induced by the fungicide triadimefon: study of the expression of TGF-beta mRNA and TGF-beta and CRABPI proteins during rat in vitro development. Toxicology and applied pharmacology 24 18976680
2021 Ero1-Pdi1 module-catalysed dimerization of a nucleotide sugar transporter, FonNst2, regulates virulence of Fusarium oxysporum on watermelon. Environmental microbiology 22 34587346
2022 Transcriptomic and metabonomic insights into the biocontrol mechanism of Trichoderma asperellum M45a against watermelon Fusarium wilt. PloS one 21 35947630
2020 Membrane disruption of Fusarium oxysporum f. sp. niveum induced by myriocin from Bacillus amyloliquefaciens LZN01. Microbial biotechnology 21 32954686
2007 Solution structure of the zinc finger HIT domain in protein FON. Protein science : a publication of the Protein Society 21 17656577
2019 Transcriptional Corepressor ASP1 and CLV-Like Signaling Regulate Meristem Maintenance in Rice. Plant physiology 20 31079034
2018 The genetic diversity within the 1.4 kb HLA-G 5' upstream regulatory region moderately impacts on cellular microenvironment responses. Scientific reports 20 29618829
2016 A Common Suite of Coagulation Proteins Function in Drosophila Muscle Attachment. Genetics 19 27585844
1999 Synthesis and characterization of lipophilic 1-[18F]fluoroalkyl-2-nitroimidazoles for imaging hypoxia. Biological & pharmaceutical bulletin 19 10408232
2015 Genetic analysis and chromosome mapping of resistance to Fusarium oxysporum f. sp. niveum (FON) race 1 and race 2 in watermelon (Citrullus lanatus L.). Molecular breeding : new strategies in plant improvement 18 26347205
2007 Antifungal triazole derivative triadimefon induces ectopic maxillary cartilage by altering the morphogenesis of the first branchial arch. Birth defects research. Part B, Developmental and reproductive toxicology 18 17187389
2017 Antifungal Activity and Action Mode of Cuminic Acid from the Seeds of Cuminum cyminum L. against Fusarium oxysporum f. sp. Niveum (FON) Causing Fusarium Wilt on Watermelon. Molecules (Basel, Switzerland) 17 29189726
2020 Endometriosis Is Associated with a Significant Increase in hTERC and Altered Telomere/Telomerase Associated Genes in the Eutopic Endometrium, an Ex-Vivo and In Silico Study. Biomedicines 16 33317189
2020 Degenerated Virulence and Irregular Development of Fusarium oxysporum f. sp. niveum Induced by Successive Subculture. Journal of fungi (Basel, Switzerland) 16 33371239
2011 The agrochemical fungicide triadimefon induces abnormalities in Xenopus laevis embryos. Reproductive toxicology (Elmsford, N.Y.) 16 21272633
2019 QTL Mapping Identifies Novel Source of Resistance to Fusarium Wilt Race 1 in Citrullus amarus. Plant disease 15 30856077
2011 Early genetic control of craniofacial development is affected by the in vitro exposure of rat embryos to the fungicide triadimefon. Birth defects research. Part B, Developmental and reproductive toxicology 15 21254369
2015 The effect of D123 wheat as a companion crop on soil enzyme activities, microbial biomass and microbial communities in the rhizosphere of watermelon. Frontiers in microbiology 14 26388851
2023 FonTup1 functions in growth, conidiogenesis and pathogenicity of Fusarium oxysporum f. sp. niveum through modulating the expression of the tricarboxylic acid cycle genes. Microbiological research 13 37099956
2023 The SUMOylation Pathway Components Are Required for Vegetative Growth, Asexual Development, Cytotoxic Responses, and Programmed Cell Death Events in Fusarium oxysporum f. sp. niveum. Journal of fungi (Basel, Switzerland) 12 36675915
2023 Fusarium oxysporum f. sp. niveum Pumilio 1 Regulates Virulence on Watermelon through Interacting with the ARP2/3 Complex and Binding to an A-Rich Motif in the 3' UTR of Diverse Transcripts. mBio 12 36856417
2022 Study on the Role of Phytohormones in Resistance to Watermelon Fusarium Wilt. Plants (Basel, Switzerland) 12 35050045
2022 Induced oxidative equilibrium damage and reduced toxin synthesis in Fusarium oxysporum f. sp. niveum by secondary metabolites from Bacillus velezensis WB. FEMS microbiology ecology 12 35776952
2022 Palmitoyl Transferase FonPAT2-Catalyzed Palmitoylation of the FonAP-2 Complex Is Essential for Growth, Development, Stress Response, and Virulence in Fusarium oxysporum f. sp. niveum. Microbiology spectrum 12 36533963
2021 Molecular Characterization of Laboratory Mutants of Fusarium oxysporum f. sp. niveum Resistant to Prothioconazole, a Demethylation Inhibitor (DMI) Fungicide. Journal of fungi (Basel, Switzerland) 12 34575742
2019 Basal Rot of Narcissus: Understanding Pathogenicity in Fusarium oxysporum f. sp. narcissi. Frontiers in microbiology 12 31921077
2016 Tuning the architectural integrity of high-performance magneto-fluorescent core-shell nanoassemblies in cancer cells. Journal of colloid and interface science 12 27388127
2023 The Extracellular Lipopeptides and Volatile Organic Compounds of Bacillus subtilis DHA41 Display Broad-Spectrum Antifungal Activity against Soil-Borne Phytopathogenic Fungi. Journal of fungi (Basel, Switzerland) 11 37623568
2021 Fusarium oxysporum f. sp. niveum Molecular Diagnostics Past, Present and Future. International journal of molecular sciences 11 34575897
2017 Inhibitory effect and mechanism of Tagetes erecta L. fungicide on Fusarium oxysporum f. sp. niveum. Scientific reports 11 29089546
2017 Bioconjugated fluorescent organic nanoparticles targeting EGFR-overexpressing cancer cells. Nanoscale 11 29135000
2012 Focused open necrosectomy in necrotizing pancreatitis. HPB : the official journal of the International Hepato Pancreato Biliary Association 11 23458703
2022 Complete genome sequence of Bacillus velezensis WB, an isolate from the watermelon rhizosphere: genomic insights into its antifungal effects. Journal of global antimicrobial resistance 10 35618208
2022 Salicylic acid remodeling of the rhizosphere microbiome induces watermelon root resistance against Fusarium oxysporum f. sp. niveum infection. Frontiers in microbiology 10 36212858
2012 Coagulation and survival in Drosophila melanogaster fondue mutants. Journal of insect physiology 10 22885376
2007 Expression and subcellular localization of E-cadherin, alpha-catenin, and beta-catenin in 8 feline mammary tumor cell lines. The Journal of veterinary medical science 10 17827890
2024 Production-optimized fermentation of antifungal compounds by bacillus velezensis LZN01 and transcriptome analysis. Microbial biotechnology 9 39415743
2021 Radiation enhances the delivery of antisense oligonucleotides and improves chemo-radiation efficacy in brain tumor xenografts. Cancer gene therapy 9 33850305
2018 A tissue communication network coordinating innate immune response during muscle stress. Journal of cell science 9 30478194
2024 The Ser/Thr protein kinase FonKin4-poly(ADP-ribose) polymerase FonPARP1 phosphorylation cascade is required for the pathogenicity of watermelon fusarium wilt fungus Fusarium oxysporum f. sp. niveum. Frontiers in microbiology 8 38690366
2022 Dual functional amphiphilic sugar-coated AIE-active fluorescent organic nanoparticles for the monitoring and inhibition of insulin amyloid fibrillation based on carbohydrate-protein interactions. Journal of materials chemistry. B 8 35801534
2021 Marker Development for Differentiation of Fusarium Oxysporum f. sp. Niveum Race 3 from Races 1 and 2. International journal of molecular sciences 8 33467563
2021 Comprehensive transcriptomic and proteomic analyses identify intracellular targets for myriocin to induce Fusarium oxysporum f. sp. niveum cell death. Microbial cell factories 8 33731109
2023 Degradation of α-Subunits, Doa1 and Doa4, are Critical for Growth, Development, Programmed Cell Death Events, Stress Responses, and Pathogenicity in the Watermelon Fusarium Wilt Fungus Fusarium oxysporum f. sp. niveum. Journal of agricultural and food chemistry 7 37486296
2023 Cyclic Lipopeptides of Bacillus amyloliquefaciens DHA6 Are the Determinants to Suppress Watermelon Fusarium Wilt by Direct Antifungal Activity and Host Defense Modulation. Journal of fungi (Basel, Switzerland) 6 37367623
2007 Characterization and identification of a novel mutant fon(t) on floral organ number and floral organ identity in rice. Journal of genetics and genomics = Yi chuan xue bao 6 17707217
2024 The SUMOylation pathway regulates the pathogenicity of Fusarium oxysporum f. sp. niveum in watermelon through stabilizing the pH regulator FonPalC via SUMOylation. Microbiological research 5 38310728
2023 Genome-Wide Association Mapping and Genomic Prediction of Fusarium Wilt Race 2 Resistance in the USDA Citrullus amarus Collection. Plant disease 5 37386705
2023 Control effect of root exudates from mycorrhizal watermelon seedlings on Fusarium wilt and the bacterial community in continuously cropped soil. Frontiers in plant science 5 37767292
2022 Niraparib treatment for patients with BRCA-mutated ovarian cancer: review of clinical data and therapeutic context. Future oncology (London, England) 5 35791804
2011 Expression analysis of some genes regulated by retinoic acid in controls and triadimefon-exposed embryos: is the amphibian Xenopus laevis a suitable model for gene-based comparative teratology? Birth defects research. Part B, Developmental and reproductive toxicology 5 21594970
2024 Mapping and validation of Fusarium wilt race 2 resistance QTL from Citrullus amarus line USVL246-FR2. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 4 38555543
2024 A Novel Strain of Fusarium oxysporum Virus 1 Isolated from Fusarium oxysporum f. sp. niveum Strain X-GS16 Influences Phenotypes of F. oxysporum Strain HB-TS-YT-1hyg. Journal of fungi (Basel, Switzerland) 4 38667923
2024 Effects of wheat intercropping on growth and occurrence of Fusarium wilt in watermelon. PeerJ 4 38952963
2021 Proteomic Analysis of Fusarium oxysporum-Induced Mechanism in Grafted Watermelon Seedlings. Frontiers in plant science 4 33747013
2023 Technological variations, microbial diversity and quality characteristics of maize ogi used for akpan production in Benin. Food research international (Ottawa, Ont.) 3 37316091
2022 Detection and Quantification of Fusarium oxysporum f. sp. niveum Race 1 in Plants and Soil by Real-time PCR. The plant pathology journal 3 35678056
2022 The Improved Biocontrol Agent, F1-35, Protects Watermelon against Fusarium Wilt by Triggering Jasmonic Acid and Ethylene Pathways. Microorganisms 3 36144312
2021 The Transcriptomic Profile of Watermelon Is Affected by Zinc in the Presence of Fusarium oxysporum f. sp. niveum and Meloidogyne incognita. Pathogens (Basel, Switzerland) 2 34201638
1999 Transplantation of fetal liver tissue suspension into the spleens of adult syngenic rats: effects of various mitogens and cytotoxins on cytochrome P450 (P450) isoforms expression and on P450 mediated monooxygenase functions. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie 2 10445401
2025 Fusarium oxysporum NAD+ hydrolase FonNADase1 is essential for pathogenicity and inhibits plant immune responses. Microbiological research 1 39955986
2025 Bacterial extracellular biomolecules-derived multimodal manganese nanoparticles control watermelon Fusarium wilt by dysregulating fusaric acid biosynthesis pathway and precise tuning of rhizosphere metabolome. Journal of nanobiotechnology 1 40533729
2025 Continuous watermelon cropping impairs plant growth by modifying soil biochemistry and rhizosphere microbial communities. Frontiers in microbiology 1 41001051
2024 Overlapping peri-implantation phenotypes of ZNHIT1 and ZNHIT2 despite distinct functions during early mouse development†. Biology of reproduction 1 39194072
2024 Poly(ADP-ribose) polymerase FonPARP1-catalyzed PARylation of protein disulfide isomerase FonPdi1 regulates pathogenicity of Fusarium oxysporum f. sp. niveum on watermelon. International journal of biological macromolecules 1 39708869
2024 The secreted protein FonCHRD is essential for vegetative growth, asexual reproduction, and pathogenicity in watermelon Fusarium wilt fungus. Crop health 1 41649655
2023 Biocontrol fungi induced stem-base rot disease resistance of Morinda officinalis How revealed by transcriptome analysis. Frontiers in microbiology 1 38107850
2022 Micronutrients Affect Expression of Induced Resistance Genes in Hydroponically Grown Watermelon against Fusarium oxysporum f. sp. niveum and Meloidogyne incognita. Pathogens (Basel, Switzerland) 1 36297194
2003 Effects of different mitogens on intrasplenic liver tissue transplants in comparison to orthotopic liver. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie 1 12877358
1998 Mitogenic short-term effects on hepatocytes and adrenocortical cells: phenobarbital and reserpine compared to carcinogenic and non-carcinogenic fluorene derivatives. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie 1 9784017
2026 Fusarium oxysporum f. sp. niveum invasion promotes Pseudomonas-driven antibiotic resistance gene enrichment. Journal of hazardous materials 0 41520435
2026 Dysregulation of neurodevelopmental regulatory networks in Anorexia Nervosa: an integrated multi-layered omics analysis. Frontiers in cell and developmental biology 0 42238894
2025 Infrared-A (IR-A) modulates the p53 pathway and diurnal clock in human skin and subcutaneous adipose tissue in vivo. Journal of photochemistry and photobiology. B, Biology 0 40482318
2025 N-terminal acetyltransferase complex FonNatA acetylates transcriptional factor FonMeaB to regulate the pathogenicity of Fusarium oxysporum f. sp. niveum on watermelon. International journal of biological macromolecules 0 40680956
2025 Gap-free comparative genomics uncover virulence factors for Fusarium wilt of watermelons. PLoS pathogens 0 40853988
2025 NO-dependent H2O2 signaling regulates melatonin-induced resistance to Fusarium oxysporum f. sp. niveum race 1 in watermelon. Plant physiology 0 41206433
2025 Genome-Wide Identification and Expression Analysis of the ClHMGB Gene Family in Watermelon Under Abiotic Stress and Fusarium oxysporum Infection. International journal of molecular sciences 0 41516034
2021 Crystal structures of three N-acyl-hydrazone isomers. Acta crystallographica. Section E, Crystallographic communications 0 34422300

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