Details for: GET4

Gene ID: 51608

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: GET4

Ensembl ID: ENSG00000239857

Description: guided entry of tail-anchored proteins factor 4

Cell Significance Landscape

Associated with

Significant Cells

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

  • CD16-positive, CD56-dim natural killer cell, human CL0000939
    CSI 7.23
    rCSI 4.82%
    PRS 97.27
  • double negative thymocyte CL0002489
    CSI 3.6
    rCSI 2.5%
    PRS 98.36
  • plasmablast CL0000980
    CSI 3.4
    rCSI 2.67%
    PRS 94.96
  • early lymphoid progenitor CL0000936
    CSI 3.36
    rCSI 2.95%
    PRS 95.97
  • secretory cell CL0000151
    CSI 2.97
    rCSI 3.1%
    PRS 92.71
  • T follicular helper cell CL0002038
    CSI 2.73
    rCSI 2.04%
    PRS 98.4
  • intermediate monocyte CL0002393
    CSI 2.72
    rCSI 4.1%
    PRS 96.62
  • granulocyte CL0000094
    CSI 2.69
    rCSI 4.12%
    PRS 96.42
  • immature B cell CL0000816
    CSI 2.48
    rCSI 1.84%
    PRS 97.45
  • astrocyte of the cerebral cortex CL0002605
    CSI 2.43
    rCSI 5.46%
    PRS 84.13
  • erythrocyte CL0000232
    CSI 2.32
    rCSI 5.26%
    PRS 91.61
  • activated CD8-positive, alpha-beta T cell, human CL0001049
    CSI 2.16
    rCSI 3.69%
    PRS 97.41
  • dopaminergic neuron CL0000700
    CSI 1.89
    rCSI 10.7%
    PRS 85.08
  • monocyte CL0000576
    CSI 1.82
    rCSI 3.29%
    PRS 94.72
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.51
    rCSI 2.43%
    PRS 84.87
  • effector memory CD8-positive, alpha-beta T cell, terminally differentiated CL0001062
    CSI 1.24
    rCSI 6.21%
    PRS 98.14
  • primitive red blood cell CL0002355
    CSI 0.9
    rCSI 4.86%
    PRS 94.12
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 0.83
    rCSI 2.02%
    PRS 81.74
  • pulmonary alveolar type 1 cell CL0002062
    CSI 0.66
    rCSI 3.82%
    PRS 91.52

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 [GET4](/details-gene/51608), or Guided Entry of Tail-anchored proteins factor 4, is a protein-coding gene located on chromosome 7p22.3. It functions as a crucial component of the cellular machinery responsible for the post-translational targeting and insertion of tail-anchored (TA) membrane proteins into the endoplasmic reticulum membrane. This process is fundamental for the proper localization and function of a wide range of proteins involved in cellular signaling, apoptosis, and vesicular transport. Consistent with this essential role, [GET4](/details-gene/51608) is broadly expressed across numerous cell types, but shows particularly high significance in various immune cells, most notably [CD16-positive, CD56-dim natural killer cell, human](/details-cell/CL0000939), suggesting a specialized requirement for TA protein handling in these lineages. ## Cellular Roles and Expression Landscape The expression profile of [GET4](/details-gene/51608) highlights its role as a broadly important, yet differentially regulated, cellular factor. **Overall**, the gene exhibits its highest significance in hematopoietic cells, indicating a critical function in the immune system. The top-ranking cell type is the [CD16-positive, CD56-dim natural killer cell, human](/details-cell/CL0000939) (CSI: 7.23), a population of cytotoxic lymphocytes, suggesting that the machinery for TA protein insertion is particularly active or vital in these cells. High significance is also observed across a spectrum of lymphoid and myeloid lineages at various developmental stages, including [double negative thymocyte](/details-cell/CL0002489), [plasmablast](/details-cell/CL0000980), [early lymphoid progenitor](/details-cell/CL0000936), [T follicular helper cell](/details-cell/CL0002038), [intermediate monocyte](/details-cell/CL0002393), and [granulocyte](/details-cell/CL0000094). This pattern suggests that [GET4](/details-gene/51608) supports fundamental processes required throughout immune cell development, activation, and effector function. The presence of highly secretory cells like [plasmablasts](/details-cell/CL0000980) in the top-ranked list is consistent with a role in managing high protein synthesis and trafficking demands. Beyond the immune system, notable significance in cell types such as [astrocyte of the cerebral cortex](/details-cell/CL0002605) and [dopaminergic neuron](/details-cell/CL0000700) underscores its ubiquitous and fundamental role in protein homeostasis across diverse tissues. ## Pathways and Molecular Function Functionally, [GET4](/details-gene/51608) is a central player in protein localization and quality control. Its primary annotated function is its involvement in the insertion of tail-anchored proteins into the endoplasmic reticulum membrane, as detailed in the Reactome pathway [R-HSA-9609523](https://reactome.org/content/detail/R-HSA-9609523) and the corresponding Gene Ontology process ([GO:0071816](https://www.ebi.ac.uk/QuickGO/term/GO:0071816)). It operates as part of a complex that recognizes the hydrophobic C-terminal anchor of newly synthesized TA proteins in the cytosol and delivers them to the ER membrane for insertion ([Link](https://doi.org/10.1038/nature09296)). In addition to protein targeting, [GET4](/details-gene/51608) is implicated in protein quality control. It participates in the ER-associated degradation (ERAD) pathway ([GO:0036503](https://www.ebi.ac.uk/QuickGO/term/GO:0036503)) and the ubiquitin-dependent protein catabolic process ([GO:0006511](https://www.ebi.ac.uk/QuickGO/term/GO:0006511)). This suggests a dual role where it not only helps correctly localize proteins but also aids in the disposal of mislocalized or unfolded proteins, thereby maintaining cellular proteostasis ([Link](https://doi.org/10.1038/nature10181); [Link](https://doi.org/10.1016/j.molcel.2011.05.010)). Its molecular function as a protein binding molecule ([GO:0005515](https://www.ebi.ac.uk/QuickGO/term/GO:0005515)) is central to these activities, allowing it to interact with other components of the GET pathway and protein chaperones. ## Research Directions The widespread yet cell-type-specific significance of [GET4](/details-gene/51608) suggests that while its core function is universal, its regulation and importance may vary depending on the specific proteomic demands of a given cell. This provides a basis for several testable hypotheses. 1. The exceptionally high significance of [GET4](/details-gene/51608) in [CD16-positive, CD56-dim natural killer cell, human](/details-cell/CL0000939) suggests that these cells have a unique dependency on specific tail-anchored proteins for their effector functions (e.g., cytotoxicity, cytokine release). It is hypothesized that targeted disruption of [GET4](/details-gene/51608) will disproportionately impair the cytotoxic capacity of NK cells compared to other immune cell types like T cells or B cells. 2. Given its role in protein quality control and the high CSI score in [plasmablasts](/details-cell/CL0000980), [GET4](/details-gene/51608) may be critical for managing proteotoxic stress associated with the massive production and secretion of antibodies. It is hypothesized that [GET4](/details-gene/51608) expression is upregulated during B cell differentiation into plasmablasts and that its inhibition would lead to ER stress and apoptosis specifically in these highly secretory cells. To test the first hypothesis regarding the role of [GET4](/details-gene/51608) in NK cell function, one could perform a CRISPR-Cas9-mediated knockout of [GET4](/details-gene/51608) in a human NK cell line (e.g., NK-92) or in primary human NK cells. The functional consequences could be assessed by measuring changes in the surface expression of key TA proteins and performing standard in vitro cytotoxicity assays against target tumor cells (e.g., K562). A significant reduction in killing efficiency in knockout cells compared to controls would validate the hypothesis. As a therapeutic target, [GET4](/details-gene/51608) appears to be a poor candidate. It is an intracellular protein involved in a fundamental housekeeping pathway essential for nearly all cell types. Systemic inhibition would likely result in widespread cellular dysfunction and high toxicity, leading to a very narrow therapeutic window. Therefore, therapeutic strategies targeting this gene are not advisable.

Genular Protein ID: 2997404854

Symbol: GET4_HUMAN

Name: Conserved edge-expressed protein

UniProtKB Accession Codes:

Q7L5D6 A4D2Q1 B3KNC7 Q9UFC9 Q9Y309

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CORUM 1 CTD 1 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 7 EMDB 3 Ensembl 2 ExpressionAtlas 1 GO 15 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 2 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 MetOSite 1 MoonDB 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 4 PDBsum 4 PIR 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 Reactome 1 RefSeq 1 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 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: 17974005

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

PubMed ID: 17974005

DOI: 10.1186/1471-2164-8-399

PubMed ID: 12690205

Title: Human chromosome 7: DNA sequence and biology.

PubMed ID: 12690205

DOI: 10.1126/science.1083423

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: 10810093

Title: Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics.

PubMed ID: 10810093

DOI: 10.1101/gr.10.5.703

PubMed ID: 18249086

Title: Genomic, evolutionary, and expression analyses of cee, an ancient gene involved in normal growth and development.

PubMed ID: 18249086

DOI: 10.1016/j.ygeno.2007.10.017

PubMed ID: 19413330

Title: Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.

PubMed ID: 19413330

DOI: 10.1021/ac9004309

PubMed ID: 20676083

Title: A ribosome-associating factor chaperones tail-anchored membrane proteins.

PubMed ID: 20676083

DOI: 10.1038/nature09296

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 21636303

Title: A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation.

PubMed ID: 21636303

DOI: 10.1016/j.molcel.2011.05.010

PubMed ID: 21743475

Title: Protein targeting and degradation are coupled for elimination of mislocalized proteins.

PubMed ID: 21743475

DOI: 10.1038/nature10181

PubMed ID: 21406692

Title: System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.

PubMed ID: 21406692

DOI: 10.1126/scisignal.2001570

PubMed ID: 22223895

Title: Comparative large-scale characterisation of plant vs. mammal proteins reveals similar and idiosyncratic N-alpha acetylation features.

PubMed ID: 22223895

DOI: 10.1074/mcp.m111.015131

PubMed ID: 22814378

Title: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB.

PubMed ID: 22814378

DOI: 10.1073/pnas.1210303109

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 25535373

Title: Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain.

PubMed ID: 25535373

DOI: 10.1073/pnas.1402745112

PubMed ID: 28104892

Title: Mechanistic basis for a molecular triage reaction.

PubMed ID: 28104892

DOI: 10.1126/science.aah6130

PubMed ID: 32395830

Title: Mutations in GET4 disrupt the transmembrane domain recognition complex pathway.

PubMed ID: 32395830

DOI: 10.1002/jimd.12249

PubMed ID: 29042515

Title: Structural basis for regulation of the nucleo-cytoplasmic distribution of Bag6 by TRC35.

PubMed ID: 29042515

DOI: 10.1073/pnas.1702940114

Sequence Information:

  • Length: 327
  • Mass: 36504
  • Checksum: 4D6C4233181B0512
  • Sequence:
    • MAAAAAMAEQ ESARNGGRNR GGVQRVEGKL RASVEKGDYY EAHQMYRTLF FRYMSQSKHT 
EARELMYSGA LLFFSHGQQN SAADLSMLVL ESLEKAEVEV ADELLENLAK VFSLMDPNSP 
ERVTFVSRAL KWSSGGSGKL GHPRLHQLLA LTLWKEQNYC ESRYHFLHSA DGEGCANMLV 
EYSTSRGFRS EVDMFVAQAV LQFLCLKNKS SASVVFTTYT QKHPSIEDGP PFVEPLLNFI 
WFLLLAVDGG KLTVFTVLCE QYQPSLRRDP MYNEYLDRIG QLFFGVPPKQ TSSYGGLLGN 
LLTSLMGSSE QEDGEESPSD GSPIELD