Details for: ZNF598

Gene ID: 90850

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: ZNF598

Ensembl ID: ENSG00000167962

Description: zinc finger protein 598, E3 ubiquitin ligase

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • common myeloid progenitor CL0000049
    CSI 7.78
    rCSI 6.29%
    PRS 98.13
  • mucosal invariant T cell CL0000940
    CSI 3.87
    rCSI 3.13%
    PRS 98.87
  • neural progenitor cell CL0011020
    CSI 3.72
    rCSI 16.36%
    PRS 90.18
  • granulocyte monocyte progenitor cell CL0000557
    CSI 3.32
    rCSI 2.87%
    PRS 98.02
  • intestine goblet cell CL0019031
    CSI 3.26
    rCSI 2.89%
    PRS 95.93
  • group 3 innate lymphoid cell CL0001071
    CSI 3.19
    rCSI 2.4%
    PRS 98.09
  • stem cell CL0000034
    CSI 3.17
    rCSI 3.06%
    PRS 95.83
  • goblet cell CL0000160
    CSI 2.95
    rCSI 2.79%
    PRS 95.94
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 2.93
    rCSI 2.26%
    PRS 98.42
  • ependymal cell CL0000065
    CSI 2.81
    rCSI 5.7%
    PRS 86.92
  • lung ciliated cell CL1000271
    CSI 2.41
    rCSI 2.79%
    PRS 94.25
  • pancreatic acinar cell CL0002064
    CSI 2.2
    rCSI 2.93%
    PRS 97.78
  • basal cell CL0000646
    CSI 2.11
    rCSI 2.83%
    PRS 95.58
  • extravillous trophoblast CL0008036
    CSI 2.07
    rCSI 2.56%
    PRS 96.05
  • club cell CL0000158
    CSI 2.06
    rCSI 3.02%
    PRS 95.63
  • small intestine goblet cell CL1000495
    CSI 1.59
    rCSI 3.48%
    PRS 97.5
  • dopaminergic neuron CL0000700
    CSI 0.86
    rCSI 4.88%
    PRS 91.2

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [ZNF598](/details-gene/90850) is a protein-coding gene located on chromosome 16p13.3 that encodes a zinc finger protein with E3 ubiquitin ligase activity. It functions as a critical sensor in ribosome-associated quality control (RQC), a cellular surveillance pathway that manages stalled ribosomes. Research indicates [ZNF598](/details-gene/90850) detects collided ribosomes, which occur during translational arrest, and subsequently ubiquitinates the 40S ribosomal subunit to initiate pathways for ribosome rescue and degradation of the nascent polypeptide chain ([Link](https://doi.org/10.1016/j.molcel.2016.12.026), [Link](https://doi.org/10.1016/j.molcel.2018.08.037)). **Overall**, expression data highlights its significance in highly proliferative or metabolically active cell types, including [common myeloid progenitor](/details-cell/CL0000049) cells, [mucosal invariant T cell](/details-cell/CL0000940)s, and various secretory epithelial cells, suggesting a fundamental role in maintaining proteostasis across diverse biological contexts. ## Cellular Roles and Expression Landscape The expression profile of [ZNF598](/details-gene/90850) points to its essential function in cells undergoing rapid proliferation, differentiation, or high rates of protein synthesis. Its highest significance is observed in hematopoietic progenitors, including [common myeloid progenitor](/details-cell/CL0000049)s (CSI: 7.78) and [granulocyte monocyte progenitor cell](/details-cell/CL0000557)s (CSI: 3.32), which is consistent with the need for robust quality control mechanisms to support the massive protein production required for lineage commitment and expansion. Beyond progenitors, [ZNF598](/details-gene/90850) is also significant in several specialized immune cell populations, such as [mucosal invariant T cell](/details-cell/CL0000940)s (CSI: 3.87) and [group 3 innate lymphoid cell](/details-cell/CL0001071)s (CSI: 3.19). This suggests a role in maintaining translational fidelity during immune activation and effector function. Furthermore, its notable expression in a wide range of secretory and barrier-forming epithelial cells, including [intestine goblet cell](/details-cell/CL0019031)s (CSI: 3.26), [lung ciliated cell](/details-cell/CL1000271)s (CSI: 2.41), and [pancreatic acinar cell](/details-cell/CL0002064)s (CSI: 2.20), underscores its importance in managing the high translational load associated with the production of mucins, enzymes, and other secreted proteins. The gene's activity in progenitor cells from different lineages, such as [neural progenitor cell](/details-cell/CL0011020)s (CSI: 3.72), further reinforces its role as a fundamental component of the cellular machinery required for proper development and tissue homeostasis. ## Pathways and Molecular Function The functions of [ZNF598](/details-gene/90850) are tightly linked to the cellular response to translational stress. Gene Ontology annotations confirm its central role in processes such as [Rescue of stalled ribosome](/details-go/GO:0072344) and [Negative regulation of translational initiation](/details-go/GO:0045947). Mechanistically, [ZNF598](/details-gene/90850) acts as a [Stalled ribosome sensor activity](/details-go/GO:0170011) that utilizes its [Ubiquitin protein ligase activity](/details-go/GO:0061630) to mediate [Protein k63-linked ubiquitination](/details-go/GO:0070534) and [Protein monoubiquitination](/details-go/GO:0006513) of ribosomal proteins ([Link](https://doi.org/10.1016/j.molcel.2016.12.026)). This ubiquitination event is a key signal that triggers the [Ribosome-associated ubiquitin-dependent protein catabolic process](/details-go/GO:1990116), ensuring the degradation of aberrant nascent proteins. The protein's molecular functions include direct [Ribosome binding](/details-go/GO:0043022) and [Rna binding](/details-go/GO:0003723), which are critical for its ability to recognize and engage with stalled ribosomal complexes in the [Cytosol](/details-go/GO:0005829). Studies have shown that this activity is particularly important for quality control of mRNAs lacking a proper stop codon, preventing the production of toxic proteins from aberrant transcripts ([Link](https://doi.org/10.1038/ncomms16056)). Additionally, [ZNF598](/details-gene/90850) has been implicated in the host antiviral response, playing distinct roles in modulating interferon-stimulated gene expression and the synthesis of poxvirus proteins ([Link](https://doi.org/10.1016/j.celrep.2018.03.132)). ## Research Directions The widespread importance of [ZNF598](/details-gene/90850) in managing translational fidelity presents several avenues for future research, particularly concerning its role in disease pathogenesis and as a potential therapeutic target. **Proposed Hypotheses:** 1. Given its high significance in hematopoietic progenitors ([common myeloid progenitor](/details-cell/CL0000049)), dysregulation or mutation of [ZNF598](/details-gene/90850) may contribute to hematopoietic malignancies by allowing the accumulation of oncogenic proteins or by impairing the proper differentiation of stem and progenitor cells under conditions of replicative stress. 2. The role of [ZNF598](/details-gene/90850) in managing translational stalls suggests it could be a critical factor in neurodegenerative diseases associated with protein aggregation. A decline in [ZNF598](/details-gene/90850) function with age may lower the threshold for proteotoxicity, accelerating disease progression. 3. Based on its role in the antiviral response ([Link](https://doi.org/10.1016/j.celrep.2018.03.132)), viruses may have evolved mechanisms to inhibit or co-opt [ZNF598](/details-gene/90850) activity to favor the translation of viral proteins over host proteins, representing a key host-pathogen battleground. **Experimental Approach:** To test the hypothesis regarding its role in hematopoiesis (Hypothesis 1), a conditional knockout of [ZNF598](/details-gene/90850) in the hematopoietic stem cell compartment of mice could be generated. These mice could then be subjected to serial bone marrow transplantation or myelosuppressive agents to assess the role of [ZNF598](/details-gene/90850) in hematopoietic self-renewal and stress hematopoiesis. The development of hematopoietic malignancies could be monitored over the animals' lifespan, and isolated progenitor cells could be analyzed using ribosome profiling (Ribo-seq) to identify specific transcripts that are sensitive to [ZNF598](/details-gene/90850) loss. **Therapeutic Potential:** As an E3 ubiquitin ligase, [ZNF598](/details-gene/90850) belongs to a class of enzymes that are amenable to small-molecule modulation. Many cancer cells are characterized by high rates of protein synthesis and aneuploidy, placing them under significant translational stress. Consequently, these cells may be more dependent on quality control pathways like RQC for survival. This dependency suggests that [ZNF598](/details-gene/90850) could be a promising therapeutic target. **Inhibition** of its ligase activity could selectively induce proteotoxic stress and apoptosis in cancer cells while sparing normal tissues, representing a potential strategy for tumors that rely on high translational throughput.

Genular Protein ID: 616349800

Symbol: ZN598_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q86UK7 Q8IW49 Q8N3D9 Q96FG3 Q9H7J3

Database IDs:

AGR 1 AlphaFoldDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CDD 1 CTD 1 ChiTaRS 1 ComplexPortal 2 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 5 GO 14 GeneCards 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 4 Pumba 1 RNAct 1 RefSeq 1 SIGNOR 1 SMART 1 STRING 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 UniPathway 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 17974005

Title: The full-ORF clone resource of the German cDNA consortium.

PubMed ID: 17974005

DOI: 10.1186/1471-2164-8-399

PubMed ID: 15592455

Title: Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.

PubMed ID: 15592455

DOI: 10.1038/nbt1046

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 19690332

Title: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.

PubMed ID: 19690332

DOI: 10.1126/scisignal.2000007

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 22751931

Title: A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development.

PubMed ID: 22751931

DOI: 10.1128/mcb.00455-12

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 28065601

Title: Initiation of quality control during poly(A) translation requires site-specific ribosome ubiquitination.

PubMed ID: 28065601

DOI: 10.1016/j.molcel.2016.11.039

PubMed ID: 28132843

Title: ZNF598 and RACK1 regulate mammalian ribosome-associated quality control function by mediating regulatory 40S ribosomal ubiquitylation.

PubMed ID: 28132843

DOI: 10.1016/j.molcel.2016.12.026

PubMed ID: 28757607

Title: Ubiquitination of stalled ribosome triggers ribosome-associated quality control.

PubMed ID: 28757607

DOI: 10.1038/s41467-017-00188-1

PubMed ID: 28685749

Title: The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs.

PubMed ID: 28685749

DOI: 10.1038/ncomms16056

PubMed ID: 29719242

Title: ZNF598 plays distinct roles in interferon-stimulated gene expression and poxvirus protein synthesis.

PubMed ID: 29719242

DOI: 10.1016/j.celrep.2018.03.132

PubMed ID: 30293783

Title: ZNF598 is a quality control sensor of collided ribosomes.

PubMed ID: 30293783

DOI: 10.1016/j.molcel.2018.08.037

PubMed ID: 32579943

Title: The ASC-1 complex disassembles collided ribosomes.

PubMed ID: 32579943

DOI: 10.1016/j.molcel.2020.06.006

PubMed ID: 32726578

Title: GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.

PubMed ID: 32726578

DOI: 10.1016/j.molcel.2020.07.007

PubMed ID: 32099016

Title: Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells.

PubMed ID: 32099016

DOI: 10.1038/s41598-020-60241-w

PubMed ID: 33581075

Title: Live-cell imaging reveals kinetic determinants of quality control triggered by ribosome stalling.

PubMed ID: 33581075

DOI: 10.1016/j.molcel.2021.01.029

PubMed ID: 36302773

Title: A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation.

PubMed ID: 36302773

DOI: 10.1038/s41467-022-34097-9

Sequence Information:

  • Length: 904
  • Mass: 98637
  • Checksum: 492F67EE4E334743
  • Sequence:
    • MAAAGGAEGR RAALEAAAAA APERGGGSCV LCCGDLEATA LGRCDHPVCY RCSTKMRVLC 
EQRYCAVCRE ELRQVVFGKK LPAFATIPIH QLQHEKKYDI YFADGKVYAL YRQLLQHECP 
RCPELPPFSL FGDLEQHMRR QHELFCCRLC LQHLQIFTYE RKWYSRKDLA RHRMQGDPDD 
TSHRGHPLCK FCDERYLDND ELLKHLRRDH YFCHFCDSDG AQDYYSDYAY LREHFREKHF 
LCEEGRCSTE QFTHAFRTEI DLKAHRTACH SRSRAEARQN RHIDLQFSYA PRHSRRNEGV 
VGGEDYEEVD RYSRQGRVAR AGTRGAQQSR RGSWRYKREE EDREVAAAVR ASVAAQQQEE 
ARRSEDQEEG GRPKKEEAAA RGPEDPRGPR RSPRTQGEGP GPKETSTNGP VSQEAFSVTG 
PAAPGCVGVP GALPPPSPKL KDEDFPSLSA STSSSCSTAA TPGPVGLALP YAIPARGRSA 
FQEEDFPALV SSVPKPGTAP TSLVSAWNSS SSSKKVAQPP LSAQATGSGQ PTRKAGKGSR 
GGRKGGPPFT QEEEEDGGPA LQELLSTRPT GSVSSTLGLA SIQPSKVGKK KKVGSEKPGT 
TLPQPPPATC PPGALQAPEA PASRAEGPVA VVVNGHTEGP APARSAPKEP PGLPRPLGSF 
PCPTPQEDFP ALGGPCPPRM PPPPGFSAVV LLKGTPPPPP PGLVPPISKP PPGFSGLLPS 
PHPACVPSPA TTTTTKAPRL LPAPRAYLVP ENFRERNLQL IQSIRDFLQS DEARFSEFKS 
HSGEFRQGLI SAAQYYKSCR DLLGENFQKV FNELLVLLPD TAKQQELLSA HTDFCNREKP 
LSTKSKKNKK SAWQATTQQA GLDCRVCPTC QQVLAHGDAS SHQALHAARD DDFPSLQAIA 
RIIT