Details for: RAET1E

Gene ID: 135250

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: RAET1E

Ensembl ID: ENSG00000164520

Description: retinoic acid early transcript 1E

Selected Context(s): 

Cell Significance Landscape

Contexts:

Associated with

  • Adaptive immune system
    (R-HSA-1280218)
  • Immune system
    (R-HSA-168256)
  • Immunoregulatory interactions between a lymphoid and a non-lymphoid cell
    (R-HSA-198933)
  • Antigen processing and presentation of endogenous peptide antigen via mhc class ib
    (GO:0002476)
  • Antigen processing and presentation of endogenous peptide antigen via mhc class i via er pathway, tap-independent
    (GO:0002486)
  • External side of plasma membrane
    (GO:0009897)
  • Extracellular space
    (GO:0005615)
  • Immune response
    (GO:0006955)
  • Natural killer cell lectin-like receptor binding
    (GO:0046703)
  • Natural killer cell mediated cytotoxicity
    (GO:0042267)
  • Plasma membrane
    (GO:0005886)
  • Positive regulation of natural killer cell mediated cytotoxicity
    (GO:0045954)
  • Positive regulation of t cell mediated cytotoxicity
    (GO:0001916)
  • Protein binding
    (GO:0005515)

Significant Cells

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

  • ciliated cell CL0000064
    CSI 6.94
    rCSI 11.25%
    PRS 99.9

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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  • Node Color (Target Cell CSI, relative to current network):
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    • 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 [RAET1E](/details-gene/135250) (Retinoic Acid Early Transcript 1E), also known as UL16-binding protein 4 (ULBP4) or NKG2D ligand 4, is a protein-coding gene located on chromosome 6q25.1. It functions as a cell surface ligand for the activating immunoreceptor NKG2D, which is expressed on [natural killer (NK) cells](/details-cell/CL0000623), CD8+ T cells, and gamma-delta T cells. The expression of [RAET1E](/details-gene/135250) on a cell surface serves as a "stress signal," marking the cell for elimination by the immune system. This mechanism is crucial for immune surveillance against virally infected and transformed cells [Link](https://doi.org/10.4161/cbt.2.4.479). The gene can produce multiple splice variants, including transmembrane forms that activate immune responses and a secreted, soluble isoform that has been shown to inhibit NK cell cytotoxicity, suggesting a role in tumor immune evasion [Link](https://doi.org/10.1074/jbc.m702504200). ## Cellular Roles and Expression Landscape The expression profile of [RAET1E](/details-gene/135250) underscores its role in mediating interactions between stressed cells and the immune system. **Overall**, analysis indicates that [RAET1E](/details-gene/135250) is a significant marker for the [ciliated cell](/details-cell/CL0000064) (CSI: 6.94). Ciliated cells form a critical barrier in tissues such as the respiratory tract, where they are a primary target for pathogens. The prominent expression of an immune-activating ligand like [RAET1E](/details-gene/135250) in this cell type suggests a key role in initiating immunosurveillance at mucosal surfaces. Upregulation of [RAET1E](/details-gene/135250) on these cells in response to viral infection or other forms of cellular distress may be a frontline mechanism for alerting NK cells and T cells to clear the compromised cells and prevent pathogen spread. ## Pathways and Molecular Function Functionally, [RAET1E](/details-gene/135250) is a non-classical MHC class I-related molecule primarily localized to the [external side of the plasma membrane](/details-ontology/GO:0009897). Its core molecular function is [natural killer cell lectin-like receptor binding](/details-ontology/GO:0046703), specifically engaging the NKG2D receptor on cytotoxic lymphocytes [Link](https://doi.org/10.1016/s0006-291x(03)00714-9). This interaction is a critical step in the [immune response](/details-ontology/GO:0006955) and leads to the [positive regulation of natural killer cell mediated cytotoxicity](/details-ontology/GO:0045954) and [positive regulation of t cell mediated cytotoxicity](/details-ontology/GO:0001916). The gene's involvement is also annotated in pathways of [antigen processing and presentation of endogenous peptide antigen via mhc class ib](/details-ontology/GO:0002476), which aligns with its role in signaling cellular state to the immune system. In the broader context of the [Immune system](/details-pathway/R-HSA-168256), [RAET1E](/details-gene/135250) is a key player in [Immunoregulatory interactions between a lymphoid and a non-lymphoid cell](/details-pathway/R-HSA-198933). ## Research Directions The dual function of [RAET1E](/details-gene/135250) isoforms—membrane-bound activators versus soluble inhibitors—presents a complex regulatory system with significant implications for both normal immune function and disease pathology. Future research should focus on the specific contexts that determine which isoform is expressed and its impact on immune outcomes. **Testable Hypotheses:** 1. Expression of [RAET1E](/details-gene/135250) on [ciliated cells](/details-cell/CL0000064) is a protective mechanism against respiratory pathogens. It is hypothesized that viral infection (e.g., by influenza virus) of airway epithelial cells induces upregulation of membrane-bound [RAET1E](/details-gene/135250), sensitizing infected cells to clearance by lung-resident NK cells. 2. The ratio of soluble-to-membrane-bound [RAET1E](/details-gene/135250) produced by a tumor dictates its susceptibility to NK cell-mediated immunotherapy. It is hypothesized that tumors with a high soluble/membrane-bound [RAET1E](/details-gene/135250) ratio will be more resistant to therapies aimed at augmenting NK cell function, as the soluble form acts as a decoy to neutralize NKG2D. **Proposed Experiment:** To test the first hypothesis, an *in vitro* co-culture model using primary human bronchial epithelial cells differentiated into a ciliated epithelium could be employed. These cells would be infected with influenza A virus, and the surface expression of [RAET1E](/details-gene/135250) would be quantified over time using flow cytometry. Subsequently, infected epithelial cells would be co-cultured with autologous NK cells. NK cell activation (CD107a surface mobilization) and target cell lysis would be measured. The specific contribution of the RAET1E-NKG2D axis would be confirmed by performing the assay in the presence of a blocking antibody against either [RAET1E](/details-gene/135250) or the NKG2D receptor and observing a reduction in NK cell activity. **Therapeutic Potential:** As a cell surface and secreted protein, [RAET1E](/details-gene/135250) presents a compelling, albeit complex, therapeutic target. A promising strategy would involve the **inhibition** of its immunosuppressive function. Specifically, developing a monoclonal antibody or small molecule that selectively neutralizes the soluble RAET1E2 isoform could be highly beneficial. Such an agent would prevent the soluble decoy from binding to NKG2D, thereby restoring the ability of NK and T cells to recognize and eliminate tumor cells expressing the membrane-bound form. This approach could disarm a key mechanism of tumor immune evasion and may synergize effectively with other immunotherapies, such as checkpoint blockade or adoptive cell transfer.

Genular Protein ID: 1198195079

Symbol: RAE1E_HUMAN

Name: NKG2D ligand 4

UniProtKB Accession Codes:

Q8TD07 A6YF59 Q5VYB7 Q5VYB8 Q8TEZ2 Q96L41

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 4 CTD 1 DNASU 1 DisGeNET 1 EMBL 8 Ensembl 4 ExpressionAtlas 1 GO 10 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 4 RNAct 1 Reactome 1 RefSeq 5 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 14508119

Title: Letal, a tumor-associated NKG2D immunoreceptor ligand, induces activation and expansion of effector immune cells.

PubMed ID: 14508119

DOI: 10.4161/cbt.2.4.479

PubMed ID: 12732206

Title: ULBP4 is a novel ligand for human NKG2D.

PubMed ID: 12732206

DOI: 10.1016/s0006-291x(03)00714-9

PubMed ID: 15240696

Title: Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D.

PubMed ID: 15240696

DOI: 10.4049/jimmunol.173.2.1078

PubMed ID: 17470428

Title: RAET1E2, a soluble isoform of the UL16-binding protein RAET1E produced by tumor cells, inhibits NKG2D-mediated NK cytotoxicity.

PubMed ID: 17470428

DOI: 10.1074/jbc.m702504200

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 14574404

Title: The DNA sequence and analysis of human chromosome 6.

PubMed ID: 14574404

DOI: 10.1038/nature02055

PubMed ID: 11827464

Title: A cluster of ten novel MHC class I related genes on human chromosome 6q24.2-q25.3.

PubMed ID: 11827464

DOI: 10.1006/geno.2001.6673

PubMed ID: 18544572

Title: Four novel ULBP splice variants are ligands for human NKG2D.

PubMed ID: 18544572

DOI: 10.1093/intimm/dxn057

Sequence Information:

  • Length: 263
  • Mass: 30122
  • Checksum: 3309279B51B603C8
  • Sequence:
    • MRRISLTSSP VRLLLFLLLL LIALEIMVGG HSLCFNFTIK SLSRPGQPWC EAQVFLNKNL 
FLQYNSDNNM VKPLGLLGKK VYATSTWGEL TQTLGEVGRD LRMLLCDIKP QIKTSDPSTL 
QVEMFCQREA ERCTGASWQF ATNGEKSLLF DAMNMTWTVI NHEASKIKET WKKDRGLEKY 
FRKLSKGDCD HWLREFLGHW EAMPEPTVSP VNASDIHWSS SSLPDRWIIL GAFILLVLMG 
IVLICVWWQN GEWQAGLWPL RTS