Affinage

ZNF16

Zinc finger protein 16 · UniProt P17020

Length
682 aa
Mass
76.5 kDa
Annotated
2026-06-11
11 papers in source corpus 7 papers cited in narrative 7 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

ZNF16 (HZF1) is a multi-C2H2 zinc finger transcription factor that couples direct DNA binding to control of cell proliferation, hematopoietic differentiation, and ribosomal RNA synthesis (PMID:19763908, PMID:24180487, PMID:41467516). It functions as a transcriptional activator with a trans-activation domain mapped to a non-zinc-finger region (aa 49–197) and nuclear localization signals within its zinc finger region (PMID:19763908). In hematopoietic cells, ZNF16 drives erythroid and megakaryocytic differentiation by binding the c-KIT promoter and repressing c-KIT, thereby blocking the c-Raf/MEK/ERK/c-Jun/HEY1 cascade and upregulating GATA1, with c-KIT knockdown rescuing the differentiation defect of ZNF16 loss (PMID:24180487). ZNF16 promotes cell proliferation by physically binding and inhibiting the CDK inhibitor INCA1, rescuing CDK2 activity and accelerating S-to-G2/M transition (PMID:21874239). It also localizes to the nucleolus in a transcription-dependent manner, binds the intergenic spacer region of rDNA, and promotes rDNA transcription, with its depletion reducing cell viability and altering cancer-associated gene expression including NRAS, BIRC3, and EGFR (PMID:41467516). Distinctly, ZNF16 acts as an antiviral factor against porcine epidemic diarrhea virus by recruiting the E3 ligase STUB1 to ubiquitinate the viral S1 protein for Tollip-mediated autophagy-lysosomal degradation (PMID:41666695).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2009 Medium

    Establishing that ZNF16 is a bona fide transcriptional activator and mapping its functional domains defined it as a regulator of gene expression rather than a structural zinc finger protein.

    Evidence Luciferase reporter, yeast auto-activation, and deletion mutagenesis in yeast and mammalian systems

    PMID:19763908

    Open questions at the time
    • No direct DNA target identified at this stage
    • Activation versus repression context not resolved
  2. 2011 Medium

    Identifying the ZNF16–INCA1 interaction explained how ZNF16 promotes proliferation through a non-transcriptional, cell-cycle-regulatory route by relieving CDK2 inhibition.

    Evidence Yeast two-hybrid screen with reciprocal Co-IP, lentiviral overexpression and cell cycle analysis in K562 cells

    PMID:21874239

    Open questions at the time
    • Mechanism by which ZNF16 inhibits INCA1 not structurally defined
    • Single cell line context
  3. 2014 High

    Demonstrating direct c-KIT promoter binding and epistatic placement upstream of c-KIT established ZNF16 as a driver of erythroid/megakaryocytic differentiation through a defined signaling cascade.

    Evidence ChIP, luciferase reporter, gain/loss-of-function and c-KIT knockdown rescue in K562 cells and primary CD34+ HSPCs

    PMID:24180487

    Open questions at the time
    • Direct DNA-binding motif not defined
    • Cofactors mediating repression unknown
  4. 2025 Medium

    Localizing ZNF16 to the nucleolus and showing it binds rDNA intergenic spacer extended its role to ribosomal RNA transcription and broad transcriptional control of cancer genes.

    Evidence Subcellular localization imaging, ChIP at rDNA, RNA-seq after knockdown, viability assays (preprint, superseded by peer-reviewed version)

    PMID:41279147

    Open questions at the time
    • Direct versus indirect effects on cancer gene expression not separated
  5. 2026 Medium

    Peer-reviewed confirmation of transcription-dependent nucleolar localization and rDNA-promoting activity solidified ZNF16's role in nucleolar function and cell viability.

    Evidence Subcellular fractionation/live imaging, ChIP at rDNA intergenic spacer, RNA-seq, viability assays across multiple cell lines

    PMID:41467516

    Open questions at the time
    • How transcription dependence drives nucleolar retention is unresolved
    • rDNA binding motif undefined
  6. 2026 Medium

    Discovery of STUB1 recruitment and Tollip-dependent degradation of viral S1 protein revealed a distinct antiviral function for ZNF16 operating through the ubiquitin-autophagy pathway.

    Evidence Protein interaction and ubiquitination assays, autophagy-lysosome inhibitor experiments, PEDV replication assays in porcine cells

    PMID:41666695

    Open questions at the time
    • Demonstrated in porcine cell context; human relevance untested
    • Direct ZNF16–STUB1 binding interface not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether ZNF16's DNA-binding/transcriptional roles and its cytoplasmic ubiquitin-adaptor antiviral role share a unified molecular logic, and what its direct genomic DNA-binding motif is, remain unresolved.
  • No consensus DNA-binding motif defined
  • No structural model of ZNF16 or its complexes
  • Tumor association (TSCC) lacks mechanistic detail

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1266738 Developmental Biology 1 R-HSA-1640170 Cell Cycle 1
Partners
INCA1STUB1

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 ZNF16 (HZF1) functions as a transcriptional activator; its trans-activation domain was mapped to amino acids 49–197 within the non-zinc-finger region, with an acidic residue-rich subregion (aa 49–105) important but insufficient alone. Three nuclear localization signals were identified within the zinc finger region at aa 255–280, 328–360, and 460–490. Luciferase reporter system, yeast auto-activation assay, deletion mutation analysis Molecular biotechnology Medium 19763908
2011 ZNF16 (HZF1) overexpression promotes K562 cell proliferation by physically interacting with INCA1 (inhibitor of CDK interacting with cyclin A1) and inhibiting its function, thereby rescuing CDK2 activity that is otherwise suppressed by INCA1. Overexpression also promoted S-to-G2/M phase transition and slightly inhibited sodium arsenate-induced apoptosis. Yeast two-hybrid screen, co-immunoprecipitation (Co-IP), lentiviral overexpression, cell cycle analysis Molecular medicine reports Medium 21874239
2014 ZNF16 promotes erythroid and megakaryocytic differentiation by binding to the c-KIT gene promoter and repressing its expression, thereby blocking the c-Raf/MEK/ERK/c-Jun/HEY1 cascade and ultimately upregulating GATA1. Knockdown of c-KIT partially rescued the differentiation defect caused by ZNF16 knockdown, establishing epistatic placement of ZNF16 upstream of c-KIT in this pathway. Luciferase reporter assay, chromatin immunoprecipitation (ChIP), gain-of-function and loss-of-function (knockdown) in K562 cells and CD34+ HSPCs, genetic epistasis (c-KIT knockdown rescue) The Biochemical journal High 24180487
2026 ZNF16 localizes to the nucleolus in a transcription-dependent manner, binds the intergenic spacer region of rDNA, and promotes rDNA transcription. ZNF16 depletion reduces cell viability across multiple cell lines and alters expression of cancer-associated genes including NRAS, BIRC3, and EGFR, implicating ZNF16 in nucleolar function and broader transcriptional regulation. Subcellular fractionation/live imaging (nucleolar localization), ChIP (rDNA intergenic spacer binding), RNA-sequencing after ZNF16 depletion, cell viability assays with knockdown Biology open Medium 41467516
2025 ZNF16 localizes to the nucleolus in a transcription-dependent manner, interacts with the intergenic spacer region of rDNA, and promotes rDNA transcription; ZNF16 depletion reduces cell viability and alters expression of cancer-associated genes (NRAS, BIRC3, EGFR) and pathways including ECM-receptor interaction, focal adhesions, and cytokine signaling. (Preprint version of PMID:41467516.) Subcellular localization imaging, ChIP (rDNA intergenic spacer), RNA-sequencing after knockdown, cell viability assays bioRxivpreprint Medium 41279147
2026 ZNF16 inhibits porcine epidemic diarrhea virus (PEDV) replication by recruiting the E3 ubiquitin ligase STUB1 to ubiquitinate the viral S1 protein; ubiquitinated S1 is then recognized by the cargo receptor Tollip and translocated to autolysosomes for degradation, suppressing viral proliferation via the autophagy-lysosome pathway. Protein interaction assays (ZNF16–STUB1 interaction), ubiquitination assay (S1 ubiquitination), autophagy-lysosome pathway inhibitor experiments, PEDV replication assay with ZNF16 overexpression/knockdown Veterinary microbiology Medium 41666695
2020 ZNF16 was identified as a novel gene mutated in tongue squamous cell carcinoma (TSCC), and in vitro experiments showed that ZNF16 promotes malignancy of TSCC cells, identifying it for the first time as a solid-tumor-associated gene. Whole-exome sequencing of tumor/normal pairs, in vitro functional assays (cell malignancy) The Journal of pathology Low 32432340

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 A homozygous deletion in a small cell lung cancer cell line involving a 3p21 region with a marked instability in yeast artificial chromosomes. Cancer research 87 8033151
2022 Genome-wide association study for milk production and conformation traits in Canadian Alpine and Saanen dairy goats. Journal of dairy science 28 36526463
2020 Exome sequencing identifies new somatic alterations and mutation patterns of tongue squamous cell carcinoma in a Chinese population. The Journal of pathology 20 32432340
2011 Zinc finger protein HZF1 promotes K562 cell proliferation by interacting with and inhibiting INCA1. Molecular medicine reports 13 21874239
2020 Expression of FAM83H and ZNF16 are associated with shorter survival of patients with gallbladder carcinoma. Diagnostic pathology 10 32460791
2009 Identification of the trans-activation domain and the nuclear location signals of human zinc finger protein HZF1 (ZNF16). Molecular biotechnology 9 19763908
2014 ZNF16 (HZF1) promotes erythropoiesis and megakaryocytopoiesis via regulation of the c-KIT gene. The Biochemical journal 7 24180487
2025 Identification of metabolism-related subtypes and feature genes of pre-eclampsia. Scientific reports 2 39930027
2026 ZNF16 is a nucleolar-associated protein that regulates expression of rDNA and cancer-associated genes. Biology open 0 41467516
2026 ZNF16 inhibits PEDV replication through autophagy-mediated degradation of S1 protein. Veterinary microbiology 0 41666695
2025 ZNF16 is a nucleolar-associated protein that regulates expression of the rDNA and cancer-associated genes. bioRxiv : the preprint server for biology 0 41279147

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