Details for: NEURL3

Gene ID: 93082

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: NEURL3

Ensembl ID: ENSG00000163121

Description: neuralized E3 ubiquitin protein ligase 3

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • secretory cell CL0000151
    CSI 4.62
    rCSI 4.82%
    PRS 99.27
  • pancreatic ductal cell CL0002079
    CSI 3.05
    rCSI 5.93%
    PRS 99.2
  • pancreatic acinar cell CL0002064
    CSI 2.8
    rCSI 3.72%
    PRS 99.15
  • club cell CL0000158
    CSI 2.22
    rCSI 3.25%
    PRS 99.39
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 1.99
    rCSI 5.16%
    PRS 99.2
  • basal cell of epithelium of trachea CL1000348
    CSI 0.77
    rCSI 5.45%
    PRS 99.51

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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  • 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 [NEURL3](/details-gene/93082) (neuralized E3 ubiquitin protein ligase 3) is a protein-coding gene located on chromosome 2q11.2 that functions as an E3 ubiquitin-protein ligase. Its activity is integral to several cellular processes, including [protein ubiquitination](https://www.ebi.ac.uk/QuickGO/term/GO:0016567) and the [innate immune response](https://www.ebi.ac.uk/QuickGO/term/GO:0045087). Research indicates that [NEURL3](/details-gene/93082) plays a direct role in host defense by promoting antiviral responses through the ubiquitination of key signaling molecules ([Link](https://doi.org/10.1096/fj.202200316r)) and by targeting viral proteins to inhibit assembly ([Link](https://doi.org/10.1128/jvi.01123-18)). **Overall**, expression data reveals that [NEURL3](/details-gene/93082) is most significant in various types of secretory and epithelial cells, particularly those of the pancreas, lung, and kidney, suggesting a specialized role in these tissues. ## Cellular Roles and Expression Landscape The expression profile of [NEURL3](/details-gene/93082) points to a significant function within tissues characterized by high secretory activity and epithelial barriers. **Overall**, the gene shows its highest significance in [secretory cell](/details-cell/CL0000151)s (CSI: 4.62), with particularly strong signals in specialized exocrine cells of the pancreas, including the [pancreatic ductal cell](/details-cell/CL0002079) (CSI: 3.05) and [pancreatic acinar cell](/details-cell/CL0002064) (CSI: 2.80). This pattern extends to other epithelial tissues that interface with the external environment or perform transport functions. High significance is observed in [club cell](/details-cell/CL0000158)s of the respiratory tract (CSI: 2.22) and [kidney loop of Henle thin ascending limb epithelial cell](/details-cell/CL1001107)s (CSI: 1.99). The notable expression in these cell types, which are involved in secretion, ion transport, and host defense, is consistent with the gene's known functions in protein modification and innate immunity. The data suggest a specialized role for [NEURL3](/details-gene/93082) in maintaining the physiological function and defense of these critical barrier tissues. ## Pathways and Molecular Function Functionally, [NEURL3](/details-gene/93082) is annotated as an E3 ligase with [ubiquitin protein ligase activity](https://www.ebi.ac.uk/QuickGO/term/GO:0061630) and the ability for [metal ion binding](https://www.ebi.ac.uk/QuickGO/term/GO:0046872), which is common for RING-type E3 ligases. Its biological activities are primarily linked to the [innate immune response](https://www.ebi.ac.uk/QuickGO/term/GO:0045087) and [protein ubiquitination](https://www.ebi.ac.uk/QuickGO/term/GO:0016567). This functional profile is strongly supported by recent studies. For instance, [NEURL3](/details-gene/93082) has been shown to catalyze the K63-linked ubiquitination of the transcription factor IRF7, a critical step in promoting an innate antiviral response ([Link](https://doi.org/10.1096/fj.202200316r)). Further evidence of its antiviral role comes from research demonstrating its ability to inhibit Hepatitis C Virus assembly by targeting the viral E1 glycoprotein for ubiquitination-dependent degradation ([Link](https://doi.org/10.1128/jvi.01123-18)). The gene product is localized to the [early endosome](https://www.ebi.ac.uk/QuickGO/term/GO:0005769), a cellular compartment consistent with its involvement in [ubiquitin-dependent endocytosis](https://www.ebi.ac.uk/QuickGO/term/GO:0070086) and the interception of viral components. ## Research Directions The high expression of [NEURL3](/details-gene/93082) in specific secretory and epithelial cell types, combined with its established role as an antiviral effector, opens several avenues for future investigation. Its function appears to be context-dependent, serving both homeostatic roles in protein regulation and inducible roles in host defense. Based on the available data, several testable hypotheses can be proposed: 1. In pancreatic exocrine cells ([pancreatic acinar cell](/details-cell/CL0002064) and [pancreatic ductal cell](/details-cell/CL0002079)), [NEURL3](/details-gene/93082) regulates the protein quality control pathway for secreted digestive enzymes, and its dysregulation could contribute to the pathology of pancreatitis by allowing the accumulation of misfolded zymogens. 2. [NEURL3](/details-gene/93082) acts as a sentinel in respiratory [club cell](/details-cell/CL0000158)s, where its expression is rapidly induced upon infection with respiratory viruses (e.g., influenza, SARS-CoV-2) to ubiquitinate specific viral or host proteins, thereby restricting viral replication and spread at this key barrier. A key experiment to test the second hypothesis would involve the use of primary human lung organoids containing [club cell](/details-cell/CL0000158)s. These organoids could be infected with Influenza A virus, and the expression of [NEURL3](/details-gene/93082) could be quantified via RT-qPCR and Western blot. To establish causality, [NEURL3](/details-gene/93082) could be knocked out using CRISPR-Cas9 in these organoids, followed by viral infection to assess changes in viral titer and host inflammatory responses. Immunoprecipitation of [NEURL3](/details-gene/93082) from infected cells followed by mass spectrometry could identify its specific viral or host protein targets. Given its function as an inducible positive regulator of the innate antiviral response, [NEURL3](/details-gene/93082) presents a potential therapeutic target. The therapeutic strategy would likely involve **activation** rather than inhibition. The development of small-molecule agonists that enhance the E3 ligase activity of [NEURL3](/details-gene/93082) could represent a novel, host-targeted approach to developing broad-spectrum antiviral agents. However, its significant expression in healthy tissues like the pancreas and kidney would necessitate careful evaluation of potential on-target toxicities.

Genular Protein ID: 1618235124

Symbol: NEUL3_HUMAN

Name: E3 ubiquitin-protein ligase NEURL3

UniProtKB Accession Codes:

Q96EH8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EC 2 EMBL 3 Ensembl 1 ExpressionAtlas 1 GO 6 Gene3D 2 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 InterPro 5 KEGG 1 MANE-Select 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 RefSeq 3 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 neXtProt 1

Citations:

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 35792897

Title: E3 ubiquitin ligase NEURL3 promotes innate antiviral response through catalyzing K63-linked ubiquitination of IRF7.

PubMed ID: 35792897

DOI: 10.1096/fj.202200316r

PubMed ID: 30111563

Title: Neuralized E3 Ubiquitin Protein Ligase 3 Is an Inducible Antiviral Effector That Inhibits Hepatitis C Virus Assembly by Targeting Viral E1 Glycoprotein.

PubMed ID: 30111563

DOI: 10.1128/jvi.01123-18

Sequence Information:

  • Length: 262
  • Mass: 28789
  • Checksum: 215410351139F515
  • Sequence:
    • MGAQLCFEAN AKAPREALRF HAEAKGAQVR LDTRGCIAHR RTTFHDGIVF SQRPVRLGER 
VALRVLREES GWCGGLRVGF TRLDPACVSV PSLPPFLCPD LEEQSPTWAA VLPEGCALTG 
DLVRFWVDRR GCLFAKVNAG CRLLLREGVP VGAPLWAVMD VYGTTKAIEL LDPTASRLPT 
PMPWDLSNKA VPEPKATPGE ECAICFYHAA NTRLVPCGHT YFCRYCAWRV FSDTAKCPVC 
RWQIEAVAPA QGPPALRVEE GS

Genular Protein ID: 2564898942

Symbol: A0A087WVI2_HUMAN

Name: N/A

UniProtKB Accession Codes:

A0A087WVI2

Database IDs:

AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID-ORCS 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 Ensembl 2 ExpressionAtlas 1 GeneTree 1 HGNC 1 HOGENOM 1 MassIVE 1 NCBI Taxonomy 1 OrthoDB 1 PeptideAtlas 1 Proteomes 2 RefSeq 1 UCSC 1 VEuPathDB 1

Citations:

PubMed ID: 11237011

Title: Initial sequencing and analysis of the human genome.

PubMed ID: 11237011

DOI: 10.1038/35057062

PubMed ID: 15496913

Title: Finishing the euchromatic sequence of the human genome.

PubMed ID: 15496913

DOI: 10.1038/nature03001

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

Sequence Information:

  • Length: 128
  • Mass: 13861
  • Checksum: 352311FE74ADF624
  • Sequence:
    • MDVYGTTKAI ELLDPTASRL PTPMPWDLSN KAVPEPKGFG PKDLALPTGN LKATWHLCLR 
EHLPTLHTRR GVCHLLLSRC QHPPCALRPH ILLQILCLAG LQRYGQVPCV PLADRGGSPC 
AGPSCSEG