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ZNF622

Cytoplasmic 60S subunit biogenesis factor ZNF622 · UniProt Q969S3

Length
477 aa
Mass
54.3 kDa
Annotated
2026-06-11
19 papers in source corpus 12 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNF622 (ZPR9) is a zinc finger protein that functions as a cytoplasmic 60S ribosomal subunit assembly factor and as a redox-sensitive signaling cofactor. In ribosome biogenesis it acts as a cofactor of DNAJC21 in 60S maturation, with its yeast ortholog Rei1 (and paralog Reh1) promoting loading of ribosomal protein eL24 onto pre-60S particles during cytoplasmic maturation (PMID:27346687, PMID:41959095). Its level is set by HectD1-mediated ubiquitination and degradation; loss of HectD1 stabilizes ZNF622 and the anti-association factor eIF6 on 60S particles, blocking 60S/40S joining and protein synthesis, and depletion of ZNF622 restores subunit joining and hematopoietic stem cell reconstitution in HectD1-deficient cells (PMID:33711283). Independently, ZNF622 is a phosphorylation-controlled activator of stress kinase signaling: it binds MPK38/MELK and ASK1 through cysteine-mediated linkages, is phosphorylated by MPK38 at Thr252 and by ASK1 at Ser314/Thr318, and in its phosphorylated state stimulates ASK1 kinase activity, drives ASK1/JNK/p38, TGF-β, and p53 signaling, and promotes oxidative-stress-induced apoptosis (PMID:21771788, PMID:28195154). Dephosphorylation at Ser143 by the phosphatase DUSP12 places ZNF622 in a cell-death pathway whose activity depends on its phosphorylation state (PMID:41851086, PMID:39868293). ZNF622 also co-activates the transcription factor B-MYB through direct interaction (PMID:12645566) and acts as an antiviral restriction factor against human adenovirus by forming a trimeric complex with viral pVII and cellular NPM1 that limits pVII-viral DNA binding and lytic virion production (PMID:30429337).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2002 Medium

    Established the first molecular partner of ZNF622, linking it to a serine/threonine kinase and to regulated nuclear localization.

    Evidence Yeast two-hybrid, co-IP and in vivo phosphorylation with MPK38/MELK

    PMID:11802789

    Open questions at the time
    • Functional consequence of MPK38 phosphorylation not defined
    • Phosphosite not mapped at this stage
  2. 2003 Medium

    Showed ZNF622 acts as a transcriptional co-activator, broadening its role beyond kinase binding.

    Evidence Yeast two-hybrid, endogenous/exogenous co-IP, reporter assay and apoptosis in neuroblastoma cells

    PMID:12645566

    Open questions at the time
    • Mechanism of B-MYB co-activation unresolved
    • Relationship between transcriptional and kinase roles unclear
  3. 2011 High

    Defined ZNF622 as a phosphorylation-dependent activator of ASK1, mapping the binding chemistry and phosphosites that control stress signaling.

    Evidence Co-IP, in vitro kinase assay, site-directed mutagenesis (Cys/Ser/Thr), AP-1 reporter and apoptosis assays

    PMID:21771788

    Open questions at the time
    • In vivo relevance of disulfide-mediated binding not tested
    • Connection to ribosomal function not addressed
  4. 2016 Medium

    Placed ZNF622 in 60S ribosomal subunit maturation as a DNAJC21 cofactor, introducing a function entirely distinct from its signaling roles.

    Evidence Co-IP, patient-derived lymphoblastoid cells, ribosome profiling

    PMID:27346687

    Open questions at the time
    • Direct biochemical role of ZNF622 in maturation not defined
    • Whether ZNF622 is required for normal ribosome assembly not shown
  5. 2017 High

    Established a reciprocal MPK38-ZNF622 activation loop and identified Thr252 as the functional phosphosite for stabilizing MPK38 and amplifying ASK1/TGF-β/p53 output.

    Evidence In vitro kinase assay, CRISPR/Cas9 T252A knockin, haploinsufficient MEFs, inducible knockdown

    PMID:28195154

    Open questions at the time
    • Tissue contexts where this loop operates not delineated
    • Integration with ribosomal function not addressed
  6. 2018 Medium

    Showed Smad proteins tune signaling output by modulating MPK38-ZNF622 complex assembly, connecting ZNF622 to TGF-β regulation.

    Evidence Co-IP, site-directed mutagenesis, adenoviral delivery in HFD mice

    PMID:29700281

    Open questions at the time
    • Direct Smad-ZNF622 contact not established
    • Mechanism of complex modulation unclear
  7. 2019 High

    Identified an antiviral function for ZNF622, restricting adenovirus via a pVII-NPM1 trimeric complex that limits viral DNA binding.

    Evidence Co-IP, ZNF622 knockout cells, virion purification, cell lysis and immunofluorescence assays

    PMID:30429337

    Open questions at the time
    • Whether restriction requires ZNF622's ribosomal or signaling activities unknown
    • Breadth of antiviral activity beyond HAdV untested
  8. 2021 High

    Defined how ZNF622 levels are controlled and the functional cost of mis-regulation, establishing it as a HectD1 ubiquitination substrate gating 60S/40S joining and protein synthesis.

    Evidence Ubiquitination assay, ribosome fractionation, genetic epistasis (Znf622 depletion in Hectd1 KO), HSC transplantation

    PMID:33711283

    Open questions at the time
    • Direct molecular interaction of ZNF622 with eIF6 on 60S not resolved
    • How ubiquitination is triggered not defined
  9. 2025 High

    Identified DUSP12 as a phosphatase acting on ZNF622 Ser143 and placed ZNF622 in a stress-induced cell-death pathway with phosphorylation-state-dependent mitotic effects.

    Evidence Affinity/proximity MS, in-cell and in-vitro IP, phosphoproteomics, phosphomutant overexpression, siRNA epistasis, apoptosis assay

    PMID:39868293 PMID:41851086

    Open questions at the time
    • Kinase responsible for Ser143 phosphorylation unidentified
    • Mechanistic basis of the mitotic defect unresolved
  10. 2026 Medium

    Defined the molecular step ZNF622's ortholog performs in ribosome maturation: loading of eL24 onto pre-60S particles upstream of subunit completion.

    Evidence MS composition analysis of pre-60S particles, genetic suppressor screen and overexpression rescue in yeast (preprint)

    PMID:41959095

    Open questions at the time
    • Direct conservation of eL24-loading role in human ZNF622 not shown
    • Preprint, not peer-reviewed
    • Structural basis of eL24 recruitment unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZNF622's ribosome-assembly function, its kinase-signaling/apoptosis roles, and its antiviral activity are coordinated within a single cell remains unresolved.
  • No unifying model linking cytoplasmic ribosome assembly to nuclear signaling functions
  • Whether distinct ZNF622 pools serve distinct functions is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1 R-HSA-392499 Metabolism of proteins 1
Partners
ASK1DNAJC21DUSP12HECTD1MPK38MYBL2NPM1SMAD4
Complex memberships
MPK38-ASK1-SMAD-TRX-ZNF622 complexZNF622-pVII-NPM1 trimeric complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 ZNF622 (ZPR9) was identified as a binding partner of murine protein serine/threonine kinase MPK38/MELK via yeast two-hybrid and co-expression assays, and is phosphorylated by MPK38 in vivo. Co-expression of ZPR9 with MPK38 caused accumulation of ZPR9 in the nucleus. Yeast two-hybrid screen, co-immunoprecipitation, in vivo phosphorylation assay, subcellular localization by co-expression The Biochemical journal Medium 11802789
2003 ZNF622 (ZPR9) physically interacts with B-MYB transcription factor through all three functional domains of B-MYB (DNA-binding domain, transactivation domain, and C-terminal conserved region), and co-expression of ZPR9 significantly upregulates B-MYB transcriptional activity in a dose-dependent manner. Co-expression also caused nuclear accumulation of both proteins. Constitutive ZPR9 expression induces apoptosis in neuroblastoma cells in the presence of retinoic acid. Yeast two-hybrid, co-immunoprecipitation of endogenous and exogenous proteins, deletion analysis, cotransfection/reporter assay, subcellular localization The Journal of biological chemistry Medium 12645566
2011 ZNF622 (ZPR9) physically interacts with apoptosis signal-regulating kinase 1 (ASK1) through a disulfide linkage involving Cys1351 and Cys1360 of ASK1 and Cys305 and Cys308 of ZPR9. ASK1 directly phosphorylates ZPR9 at Ser314 and Thr318. Wild-type ZPR9, but not S314A/T318A mutant, stimulates ASK1 kinase activity, promotes ASK1-mediated signaling to JNK and p38 by destabilizing ASK1-Trx and ASK1-14-3-3 inhibitory complexes and by increasing ASK1-MKK3 complex formation, and promotes H2O2-mediated apoptosis in a phosphorylation-dependent manner. ZPR9 also inhibits PDK1-mediated signaling through ASK1 activation. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, reporter assay (AP-1), apoptosis assay, knockdown The Journal of biological chemistry High 21771788
2016 ZNF622 (ZPR9) is a cofactor of DNAJC21 involved in 60S ribosomal subunit maturation. DNAJC21 mutations impair its interaction with ZNF622, PA2G4, and HSPA8. DNAJC21 deficiency results in cytoplasmic accumulation of PA2G4, aberrant ribosome profiles, and increased cell death. Co-immunoprecipitation, functional interaction studies with patient-derived lymphoblastoid cells, ribosome profiling American journal of human genetics Medium 27346687
2016 ZNF622 (ZPR9) is a component of a multiprotein complex with MPK38, ASK1, SMADs, and thioredoxin (TRX) that coordinately regulates redox-dependent ASK1 and TGF-β signaling pathways. Adenoviral delivery of ZPR9 in obese mice restored downregulated ASK1 and TGF-β signaling and ameliorated adiposity, hyperglycemia, hyperlipidemia, and impaired ketogenesis. Co-immunoprecipitation (multiprotein complex), adenoviral overexpression in mice, metabolic phenotyping Antioxidants & redox signaling Medium 26421442
2017 ZNF622 (ZPR9) functions as an activator of MPK38, with the interaction mediated by cysteine residues (Cys269 and Cys286 of MPK38; Cys305 and Cys308 of ZPR9). MPK38 phosphorylates ZPR9 at Thr252; wild-type ZPR9 but not T252A mutant enhances ASK1, TGF-β, and p53 function by stabilizing MPK38. This was validated using CRISPR/Cas9-mediated ZPR9(T252A) knockin cell lines, haploinsufficient MEF cells, and inducible knockdown systems. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, CRISPR/Cas9 knockin, haploinsufficient MEF cells, inducible shRNA knockdown Scientific reports High 28195154
2018 Smad proteins differentially regulate MPK38 activity partly through modulating complex formation between MPK38 and ZPR9 (ZNF622): Smads2/3/4 increased while Smad7 decreased MPK38-ZPR9 complex formation. Phosphorylation-defective Smad mutants abolished these effects. Co-immunoprecipitation, site-directed mutagenesis, adenoviral delivery in HFD mice Cell death & disease Medium 29700281
2019 ZNF622 acts as a cellular antiviral protein against human adenovirus (HAdV). ZNF622 forms a trimeric complex with viral pVII protein and cellular nucleophosmin 1 (NPM1). Loss of ZNF622 increases pVII binding to viral DNA and pVII levels in purified virions, enhances cell lysis, and increases infectious virion accumulation. ZNF622 accumulated in nuclei of virus-infected cells. ZNF622 mutations and NPM1 deficiency altered pVII's ability to bind viral DNA. Protein interaction studies (co-IP), ZNF622 knockout cells, virion purification and quantification, cell lysis assay, immunofluorescence localization Journal of virology High 30429337
2021 HectD1 E3 ubiquitin ligase ubiquitinates and degrades ZNF622, an assembly factor for the ribosomal 60S subunit. Loss of HectD1 leads to accumulation of ZNF622 and the anti-association factor eIF6 on 60S, causing 60S/40S joining defects and reduced protein synthesis. Depletion of ZNF622 in Hectd1-deficient HSCs restored ribosomal subunit joining, protein synthesis, and HSC reconstitution capacity. Ubiquitination assay, ribosome fractionation, genetic epistasis (Znf622 depletion in Hectd1 KO), protein synthesis measurement, HSC transplantation assay Cell stem cell High 33711283
2025 DUSP12 interacts with ZNF622 (ZPR9) via its unique zinc-binding domain. DUSP12 overexpression promotes de-phosphorylation of ZNF622 at Ser143. ZNF622 overexpression causes pre-metaphase mitotic defects dependent on Ser143 phosphorylation state (phosphomimetic and phosphorylation-deficient mutants did not). Knockdown of DUSP12 promoted stress-induced apoptosis, while knockdown of ZNF622 suppressed it, placing ZNF622 downstream of DUSP12 in a cell death pathway. Affinity- and proximity-based biochemical purification coupled to mass spectrometry, in-cell and in-vitro IP assays, phosphoproteomic analysis, ZNF622 overexpression with phosphomutants, siRNA knockdown, apoptosis assay Cell death & disease High 39868293 41851086
2026 In yeast, Rei1 (ZNF622 ortholog) and its paralog Reh1 facilitate loading of ribosomal protein eL24 onto pre-60S particles in the cytoplasm. Pre-60S subunits from rei1Δ reh1Δ cells are specifically deficient in eL24. eL24 overexpression suppresses the growth defect of the double mutant. Suppressors of rei1Δ reh1Δ growth defects (mutations in uL3, Lsg1, Ppq1) partially reverse the eL24 loading defect, establishing that Rei1/Reh1 act upstream of eL24 recruitment during cytoplasmic 60S maturation. Protein composition analysis of isolated pre-60S particles (MS), genetic suppressor screen, overexpression rescue bioRxivpreprint Medium 41959095

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation. American journal of human genetics 95 27346687
2021 Multi-level inhibition of coronavirus replication by chemical ER stress. Nature communications 87 34545074
2021 HectD1 controls hematopoietic stem cell regeneration by coordinating ribosome assembly and protein synthesis. Cell stem cell 59 33711283
2002 Phosphorylation of a novel zinc-finger-like protein, ZPR9, by murine protein serine/threonine kinase 38 (MPK38). The Biochemical journal 40 11802789
2018 Smad proteins differentially regulate obesity-induced glucose and lipid abnormalities and inflammation via class-specific control of AMPK-related kinase MPK38/MELK activity. Cell death & disease 36 29700281
2003 Enhancement of B-MYB transcriptional activity by ZPR9, a novel zinc finger protein. The Journal of biological chemistry 36 12645566
2018 Altered DNA Methylation Sites in Peripheral Blood Leukocytes from Patients with Simple Steatosis and Nonalcoholic Steatohepatitis (NASH). Medical science monitor : international medical journal of experimental and clinical research 25 30270343
2017 Zinc finger protein ZPR9 functions as an activator of AMPK-related serine/threonine kinase MPK38/MELK involved in ASK1/TGF-β/p53 signaling pathways. Scientific reports 23 28195154
2014 A crucial role for the phosphorylation of STRAP at Ser(188) by MPK38 in STRAP-dependent cell death through ASK1, TGF-β, p53, and PI3K/PDK1 signaling pathways. Cell cycle (Georgetown, Tex.) 23 25485581
2020 Genome-wide detection of copy number variants in European autochthonous and commercial pig breeds by whole-genome sequencing of DNA pools identified breed-characterising copy number states. Animal genetics 21 32510676
2016 Coordinate Activation of Redox-Dependent ASK1/TGF-β Signaling by a Multiprotein Complex (MPK38, ASK1, SMADs, ZPR9, and TRX) Improves Glucose and Lipid Metabolism in Mice. Antioxidants & redox signaling 18 26421442
2011 Positive regulation of apoptosis signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger protein. The Journal of biological chemistry 17 21771788
2019 Cellular Zinc Finger Protein 622 Hinders Human Adenovirus Lytic Growth and Limits Binding of the Viral pVII Protein to Virus DNA. Journal of virology 12 30429337
2024 Human cells contain myriad excised linear intron RNAs with links to gene regulation and potential utility as biomarkers. PLoS genetics 7 39325823
2026 DUSP12 promotes cell cycle progression and protects cells from ZNF622 mediated apoptosis. Cell death & disease 1 41851086
2025 DUSP12 promotes cell cycle progression and protects cells from cell death by regulating ZPR9. bioRxiv : the preprint server for biology 1 39868293
2026 Rei1 and Reh1 facilitate the loading of eL24. bioRxiv : the preprint server for biology 0 41959095
2025 Gonadal sex differentiation in Eleutheronema tetradactylum: Histological features and transcriptomic insights from mature gonads. Comparative biochemistry and physiology. Part D, Genomics & proteomics 0 40694934
2021 Releasing the brake on protein synthesis in hematopoietic stem cells. Cell stem cell 0 34214436

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