Details for: SPATA2

Gene ID: 9825

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: SPATA2

Ensembl ID: ENSG00000158480

Description: spermatogenesis associated 2

Cell Significance Landscape

Associated with

Significant Cells

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

  • goblet cell CL0000160
    CSI 3.97
    rCSI 3.75%
    PRS 98.7
  • ependymal cell CL0000065
    CSI 2.69
    rCSI 5.46%
    PRS 94.16
  • cerebral cortex neuron CL0010012
    CSI 2.62
    rCSI 10.68%
    PRS 96.25
  • VIP GABAergic cortical interneuron CL4023016
    CSI 2.49
    rCSI 2.98%
    PRS 96.52
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.33
    rCSI 2.89%
    PRS 96.17
  • retinal cone cell CL0000573
    CSI 2.29
    rCSI 3.69%
    PRS 96.85
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.26
    rCSI 2.91%
    PRS 97.05
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.88
    rCSI 3.16%
    PRS 96.95
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.1
    rCSI 2.68%
    PRS 95.54
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.8
    rCSI 2.89%
    PRS 95.97

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.

Comma-separated if multiple.
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 Analyzed for its expression specificity (CSI Z-SCORE), Spermatogenesis Associated 2 ([SPATA2](/details-gene/9825)) is a broadly expressed adaptor protein that lacks unique enrichment in any single cell type. Instead, its consistent expression across diverse lineages, including various neurons and epithelial cells, highlights its fundamental role in a ubiquitous and critical signaling pathway. [SPATA2](/details-gene/9825) is a key component of the tumor necrosis factor (TNF) receptor signaling complex, where it functions to link the deubiquitinase CYLD to the linear ubiquitin chain assembly complex (LUBAC), thereby regulating the cellular decision between pro-inflammatory NF-kappaB activation and apoptosis or necroptosis. ## Cellular Roles and Expression Landscape The expression profile of [SPATA2](/details-gene/9825), when evaluated for cell-type specificity, reveals a pattern of broad, rather than restricted, expression. In the **Overall** context, the CSI (Z-SCORE) is 0.00 with non-significant p-values (p > 0.6) across all top-ranked cell types. This indicates that [SPATA2](/details-gene/9825) is not a defining marker gene for any specific cell population. However, its high Percentile Rank Score (PRS > 94%) in cell types as distinct as [goblet cells](/details-cell/CL0000160), [ependymal cells](/details-cell/CL0000065), and a wide array of central nervous system neurons (e.g., [cerebral cortex neuron](/details-cell/CL0010012), [pvalb GABAergic cortical interneuron](/details-cell/CL4023018)) suggests that it is a relatively abundant transcript within these cells. This combination of low specificity and high relative abundance is consistent with a protein that performs a crucial, housekeeping-like function in a widely active signaling pathway. The presence of [SPATA2](/details-gene/9825) across epithelial, glial, and diverse neuronal subtypes underscores the universal importance of tightly regulating TNF signaling throughout the body. ## Pathways and Molecular Function The broad expression pattern of [SPATA2](/details-gene/9825) is directly explained by its central role in TNF signaling ([R-HSA-75893](https://reactome.org/content/detail/R-HSA-75893)), a pathway fundamental to immunity, inflammation, and cell survival. Functionally, [SPATA2](/details-gene/9825) acts as a signaling receptor complex adaptor ([GO:0030159](https://www.ebi.ac.uk/QuickGO/term/GO:0030159)) located in the cytoplasm ([GO:0005737](https://www.ebi.ac.uk/QuickGO/term/GO:0005737)). Its primary described mechanism involves mediating the interaction between other signaling proteins. Seminal studies have shown that [SPATA2](/details-gene/9825) forms a trimeric complex with the deubiquitinase CYLD and the catalytic subunit of LUBAC, HOIP (Wagner et al., *Mol Cell*, 2016, [DOI: 10.1016/j.molcel.2016.08.001](https://doi.org/10.1016/j.molcel.2016.08.001); Schlicher et al., *EMBO Rep*, 2016, [DOI: 10.15252/embr.201642592](https://doi.org/10.15252/embr.201642592); Kupka et al., *Cell Rep*, 2016, [DOI: 10.1016/j.celrep.2016.07.086](https://doi.org/10.1016/j.celrep.2016.07.086)). By recruiting CYLD to the TNFR1 signaling complex, [SPATA2](/details-gene/9825) facilitates the removal of K63-linked and linear ubiquitin chains from key substrates like RIPK1. This action is a critical checkpoint, modulating the balance between NF-kappaB-mediated pro-survival signaling and the induction of programmed cell death, including the necroptotic process ([GO:0070266](https://www.ebi.ac.uk/QuickGO/term/GO:0070266)). While originally characterized in the context of spermatogenesis ([GO:0007283](https://www.ebi.ac.uk/QuickGO/term/GO:0007283)) (Yoo et al., *Exp Cell Res*, 1999, [DOI: 10.1006/excr.1999.4449](https://doi.org/10.1006/excr.1999.4449)), its function is now understood to be pleiotropic. ## Research Directions The ubiquitous expression of [SPATA2](/details-gene/9825) combined with its critical role as a signaling rheostat presents several avenues for future investigation. The key question is how a universally expressed protein contributes to context-specific cellular outcomes. ### Testable Hypotheses: 1. **Hypothesis:** The regulatory activity of the [SPATA2](/details-gene/9825)-CYLD complex is determined not by transcriptional abundance but by cell-type-specific post-translational modifications (PTMs) on [SPATA2](/details-gene/9825). These PTMs could alter its affinity for CYLD or LUBAC, thereby tuning the response to TNF stimulation in different cellular environments, such as neurons versus epithelial cells. * **Experimental Approach:** Employ affinity purification-mass spectrometry (AP-MS) on tagged [SPATA2](/details-gene/9825) expressed in different cell lines (e.g., neuronal SH-SY5Y vs. intestinal Caco-2). Compare the PTM landscape (phosphorylation, ubiquitination) and the composition of the [SPATA2](/details-gene/9825) interactome at baseline and following TNF-alpha treatment to identify cell-specific regulatory events. 2. **Hypothesis:** In the central nervous system, where [SPATA2](/details-gene/9825) is abundantly expressed in various neurons, it acts as a critical neuroprotective factor by suppressing TNF-induced necroptosis. A decline in [SPATA2](/details-gene/9825) function or expression with age or disease could lower the threshold for neuroinflammation-driven cell death, contributing to the pathology of neurodegenerative diseases. * **Experimental Approach:** Create a neuron-specific conditional knockout of [SPATA2](/details-gene/9825) in mice (e.g., using a Syn1-Cre driver). Subject these mice and their wild-type littermates to a model of neuroinflammation (e.g., intracerebroventricular LPS injection) and quantify neuronal loss, glial activation, and necroptotic markers (p-MLKL) in the cortex and hippocampus. 3. **Hypothesis:** In intestinal [goblet cells](/details-cell/CL0000160), [SPATA2](/details-gene/9825) is essential for maintaining mucosal barrier integrity during active inflammation. By promoting CYLD-mediated deubiquitination, it protects these critical mucus-secreting cells from TNF-induced apoptosis, and its dysregulation could be a contributing factor in inflammatory bowel disease (IBD). * **Experimental Approach:** Generate intestinal organoids from `Spata2`-floxed mice and induce goblet cell differentiation. Use a tamoxifen-inducible Cre system to delete [SPATA2](/details-gene/9825) and then challenge the organoids with TNF-alpha and IFN-gamma. Measure goblet cell viability, mucus layer integrity (via Alcian Blue/PAS staining), and barrier function using a fluorescent dextran exclusion assay. ### Therapeutic Potential: Given its central role in modulating TNF signaling, the [SPATA2](/details-gene/9825)-CYLD-LUBAC axis represents a promising therapeutic target. Direct inhibition of the broadly expressed [SPATA2](/details-gene/9825) may cause significant side effects. A more refined strategy would be to develop small molecules or biologics that specifically modulate the protein-protein interactions within this complex. For example, a therapeutic designed to stabilize the SPATA2-CYLD interaction could potentiate anti-inflammatory and anti-necroptotic activity, which may be beneficial in treating chronic inflammatory disorders like rheumatoid arthritis or IBD. Conversely, disrupting this interaction could sensitize cancer cells to TNF-induced apoptosis, offering a potential strategy for combination cancer therapy.

Genular Protein ID: 3280840594

Symbol: SPAT2_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q9UM82 E1P626 O94857

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CORUM 1 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 6 Ensembl 2 GO 15 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 1 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 3 RefSeq 4 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10222154

Title: cDNA cloning and characterization of PD1: a novel human testicular protein with different expressions in various testiculopathies.

PubMed ID: 10222154

DOI: 10.1006/excr.1999.4449

PubMed ID: 9872452

Title: Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.

PubMed ID: 9872452

DOI: 10.1093/dnares/5.5.277

PubMed ID: 11780052

Title: The DNA sequence and comparative analysis of human chromosome 20.

PubMed ID: 11780052

DOI: 10.1038/414865a

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: 11079456

Title: A novel gene (PD1) with a potential role on rat spermatogenesis.

PubMed ID: 11079456

DOI: 10.1007/bf03343783

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: 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: 27307491

Title: SPATA2 links CYLD to the TNF-alpha receptor signaling complex and modulates the receptor signaling outcomes.

PubMed ID: 27307491

DOI: 10.15252/embj.201694300

PubMed ID: 27458237

Title: SPATA2 promotes CYLD activity and regulates TNF-induced NF-kappaB signaling and cell death.

PubMed ID: 27458237

DOI: 10.15252/embr.201642592

PubMed ID: 27545878

Title: SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes.

PubMed ID: 27545878

DOI: 10.1016/j.celrep.2016.07.086

PubMed ID: 28189684

Title: Decreased linear ubiquitination of NEMO and FADD on apoptosis with caspase-mediated cleavage of HOIP.

PubMed ID: 28189684

DOI: 10.1016/j.bbrc.2017.02.040

PubMed ID: 27591049

Title: SPATA2 links CYLD to LUBAC, activates CYLD, and controls LUBAC signaling.

PubMed ID: 27591049

DOI: 10.1016/j.molcel.2016.08.001

Sequence Information:

  • Length: 520
  • Mass: 58427
  • Checksum: D29869B601166C89
  • Sequence:
    • MGKPSSMDTK FKDDLFRKYV QFHESKVDTT TSRQRPGSDE CLRVAASTLL SLHKVDPFYR 
FRLIQFYEVV ESSLRSLSSS SLRALHGAFS MLETVGINLF LYPWKKEFRS IKTYTGPFVY 
YVKSTLLEED IRAILSCMGY TPELGTAYKL RELVETLQVK MVSFELFLAK VECEQMLEIH 
SQVKDKGYSE LDIVSERKSS AEDVRGCSDA LRRRAEGREH LTASMSRVAL QKSASERAAK 
DYYKPRVTKP SRSVDAYDSY WESRKPPLKA SLSLRKEPVA TDVGDDLKDE IIRPSPSLLT 
MASSPHGSPD VLPPASPSNG PALLRGTYFS TQDDVDLYTD SEPRATYRRQ DALRPDVWLL 
RNDAHSLYHK RSPPAKESAL SKCQSCGLSC SSSLCQRCDS LLTCPPASKP SAFPSKASTH 
DSLAHGASLR EKYPGQTQGL DRLPHLHSKS KPSTTPTSRC GFCNRPGATN TCTQCSKVSC 
DACLSAYHYD PCYKKSELHK FMPNNQLNYK STQLSHLVYR

Genular Protein ID: 1825403276

Symbol: A8K0S9_HUMAN

Name: N/A

UniProtKB Accession Codes:

A8K0S9

Database IDs:

ARBA 1 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 GO 5 Gene3D 1 InterPro 1 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PeptideAtlas 1 Pfam 2 PharmGKB 1 RefSeq 1 SAM 1

Sequence Information:

  • Length: 520
  • Mass: 58499
  • Checksum: CDD269B601166C15
  • Sequence:
    • MEKPSSMDTK FKDDLFRKYV QFHESKVDTT TSRQRPGSDE CLRVAASTLL SLHKVDPFYR 
FRLIQFYEVV ESSLRSLSSS SLRALHGAFS MLETVGINLF LYPWKKEFRS IKTYTGPFVY 
YVKSTLLEED IRAILSCMGY TPELGTAYKL RELVETLQVK MVSFELFLAK VECEQMLEIH 
SQVKDKGYSE LDIVSERKSS AEDVRGCSDA LRRRAEGREH LTASMSRVAL QKSASERAAK 
DYYKPRVTKP SRSVDAYDSY WESRKPPLKA SLSLRKEPVA TDVGDDLKDE IIRPSPSLLT 
MASSPHGSPD VLPPASPSNG PALLRGTYFS TQDDVDLYTD SEPRATYRRQ DALRPDVWLL 
RNDAHSLYHK RSPPAKESAL SKCQSCGLSC SSSLCQRCDS LLTCPPASKP SAFPSKASTH 
DSLAHGASLR EKYPGQTQGL DRLPHLHSKS KPSTTPTSRC GFCNRPGATN TCTQCSKVSC 
DACLSAYHYD PCYKKSELHK FMPNNQLNYK STQLSHLVYR

Genular Protein ID: 1347336986

Symbol: B4DID4_HUMAN

Name: N/A

UniProtKB Accession Codes:

B4DID4

Database IDs:

ARBA 1 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 GO 5 Gene3D 1 InterPro 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PeptideAtlas 1 Pfam 2 PharmGKB 1 RefSeq 1 SAM 1

Sequence Information:

  • Length: 383
  • Mass: 42464
  • Checksum: EE7657B34392D0FC
  • Sequence:
    • MGYTPELGTA YKLRELVETL QVKMVSFELF LAKVECEQML EIHSQVKDKG YSELDIVSER 
KSSAEDVRGC SDALRRRAEG REHLTASMSR VALQKSASER AAKDYYKPRV TKPSRSVDAY 
DSYWESRKPP LKASLSLRKE PVATDVGDDL KDEIIRPSPS LLTMASSPHG SPDVLPPASP 
SNGPALLRGT YFSTQDDVDL YTDSEPRATY RRQDALRPDV WLLRNDAHSL YHKRSPPAKE 
SALSKCQSCG LSCSSSLCQR CDSLLTCPPA SKPSAFPSKA STHDSLAHGA SLREKYPGQT 
QGLDRLPHLH SKSKPSTTPT SRCGFCNRPG ATNTCTQCSK VSCDACLSAY HYDPCYKKSE 
LHKFMPNNQL NYKSTQLSHL VYG