Details for: SPINK8

Gene ID: 646424

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: SPINK8

Ensembl ID: ENSG00000229453

Description: serine peptidase inhibitor Kazal type 8 (putative)

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • regulatory T cell CL0000815
    CSI 32.08
    rCSI 37.19%
    PRS 97.9
  • helper T cell CL0000912
    CSI 19.13
    rCSI 27.05%
    PRS 98.55
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 17.75
    rCSI 21.51%
    PRS 95.78
  • melanocyte of skin CL1000458
    CSI 15.56
    rCSI 21.21%
    PRS 95.57
  • cerebral cortex endothelial cell CL1001602
    CSI 13.86
    rCSI 23.97%
    PRS 99.66
  • basal cell of epidermis CL0002187
    CSI 13.7
    rCSI 24.28%
    PRS 94.23
  • innate lymphoid cell CL0001065
    CSI 5.81
    rCSI 12.01%
    PRS 98.53
  • cytotoxic T cell CL0000910
    CSI 5.64
    rCSI 32.33%
    PRS 98.71
  • suprabasal keratinocyte CL4033013
    CSI 2.15
    rCSI 3.51%
    PRS 95.77
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 2.05
    rCSI 7.39%
    PRS 99.21
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 2.04
    rCSI 7.72%
    PRS 99.17

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

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
    • Medium
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    • 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 [SPINK8](/details-gene/646424) is a protein-coding gene located on chromosome 3p21.31, which encodes a putative serine peptidase inhibitor of the Kazal type family. Functionally, it is annotated as being involved in the [negative regulation of peptidase activity](/details-go/GO:0010466) and exhibits [serine-type endopeptidase inhibitor activity](/details-go/GO:0004867). As an extracellular protein, it likely modulates proteolytic cascades in the cellular microenvironment. Expression data from an **Overall** biological context reveals a highly specific and significant role for [SPINK8](/details-gene/646424) in the immune system, particularly in T cell subsets, with the highest significance observed in [regulatory T cell](/details-cell/CL0000815). Additionally, it shows notable significance in various skin cell types, including [melanocyte of skin](/details-cell/CL1000458) and [basal cell of epidermis](/details-cell/CL0002187), suggesting a dual role in both immunomodulation and cutaneous homeostasis. ## Cellular Roles and Expression Landscape The expression profile of [SPINK8](/details-gene/646424) points to a specialized function in distinct cellular compartments, primarily within the adaptive immune system and the skin. **Overall**, the gene's most prominent role is within the T lymphocyte lineage. It is a highly significant marker for [regulatory T cell](/details-cell/CL0000815) (CSI: 32.08), where its significance far exceeds that in other cell types. It is also highly expressed in [helper T cell](/details-cell/CL0000912) (CSI: 19.13) and [CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203) (CSI: 17.75), with moderate significance in [innate lymphoid cell](/details-cell/CL0001065) and [cytotoxic T cell](/details-cell/CL0000910). This pattern suggests that [SPINK8](/details-gene/646424) may be involved in regulating T cell function, activation, or differentiation, with a particularly crucial role in the suppressive activity of regulatory T cells. A second major site of [SPINK8](/details-gene/646424) expression is the skin. It demonstrates high significance in both [melanocyte of skin](/details-cell/CL1000458) (CSI: 15.56) and [basal cell of epidermis](/details-cell/CL0002187) (CSI: 13.70), as well as in [suprabasal keratinocyte](/details-cell/CL4033013). This co-expression in multiple epidermal cell types suggests a potential role in maintaining skin barrier function, regulating desquamation, or modulating inflammatory responses in the cutaneous microenvironment. Lesser, but still notable, significance is seen in [cerebral cortex endothelial cell](/details-cell/CL1001602) and certain neuronal subtypes, indicating potential secondary roles in vascular or neural biology, although these are less pronounced than its functions in immunity and skin. ## Pathways and Molecular Function The known molecular function of [SPINK8](/details-gene/646424) aligns well with its cellular expression profile. As an extracellular ([GO:0005576](https://www.ebi.ac.uk/QuickGO/term/GO:0005576)) inhibitor of serine-type endopeptidases ([GO:0004867](https://www.ebi.ac.uk/QuickGO/term/GO:0004867)), it is positioned to regulate a wide array of biological processes governed by proteolysis. In the context of its high expression in T cells, particularly [regulatory T cell](/details-cell/CL0000815), [SPINK8](/details-gene/646424) may inhibit proteases such as granzymes or other T-cell-secreted enzymes that mediate cytotoxicity or inflammation. By locally neutralizing these proteases, [SPINK8](/details-gene/646424) could contribute to the immunosuppressive function characteristic of regulatory T cells. In the skin, a delicate balance between proteases (e.g., kallikreins) and their inhibitors is critical for epidermal turnover and barrier function. The high expression of [SPINK8](/details-gene/646424) in keratinocytes and melanocytes suggests it may be a key regulator in this system, preventing excessive proteolysis that could otherwise lead to skin barrier defects or inflammation. The gene's role was first established as part of large-scale genome annotation projects ([Link](https://doi.org/10.1038/nature04728); [Link](https://doi.org/10.1101/gr.2596504)). ## Research Directions The specific and high-level expression of [SPINK8](/details-gene/646424) in key immunoregulatory and epithelial cells warrants further investigation into its precise biological roles and therapeutic potential. **Proposed Hypotheses:** 1. **Role in Treg-mediated Immunosuppression:** The exceptionally high significance in [regulatory T cell](/details-cell/CL0000815) suggests that [SPINK8](/details-gene/646424) is a key secreted effector molecule contributing to their suppressive function. It may act by inhibiting proteases required for the activation, proliferation, or migration of conventional effector T cells within the same microenvironment. 2. **Maintenance of Epidermal Homeostasis:** The strong expression of [SPINK8](/details-gene/646424) in multiple skin cell layers indicates it is a critical regulator of cutaneous protease activity. Its deficiency may lead to impaired skin barrier function, abnormal desquamation, and increased susceptibility to inflammatory skin diseases like atopic dermatitis or psoriasis due to unchecked protease-mediated signaling. **Experimental Approach:** To test the first hypothesis regarding its role in Treg function, a conditional knockout mouse model could be generated where [SPINK8](/details-gene/646424) is specifically deleted in Foxp3-expressing regulatory T cells. The function of these SPINK8-deficient Tregs could be assessed using in vitro co-culture suppression assays with effector T cells. In vivo, these mice could be challenged in models of autoimmunity (e.g., experimental autoimmune encephalomyelitis) or tumor immunity to determine if the loss of [SPINK8](/details-gene/646424) in Tregs impairs their ability to control immune responses, leading to exacerbated autoimmunity or enhanced anti-tumor immunity. **Therapeutic Potential:** [SPINK8](/details-gene/646424)'s role as a secreted protein inhibitor makes it an attractive therapeutic target. In oncology, where Treg-mediated suppression often hinders anti-tumor immunity, **inhibition** of [SPINK8](/details-gene/646424) via a monoclonal antibody could disarm this suppressive mechanism and synergize with other immunotherapies. Conversely, in autoimmune or inflammatory skin diseases potentially driven by excessive protease activity, **activation** or supplementation with a recombinant [SPINK8](/details-gene/646424) protein could serve as a novel anti-inflammatory therapeutic by restoring proteolytic balance.

Genular Protein ID: 2951360620

Symbol: ISK8_HUMAN

Name: Serine protease inhibitor Kazal-type 8

UniProtKB Accession Codes:

P0C7L1

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 2 Ensembl 1 GO 2 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 InterPro 2 KEGG 1 MANE-Select 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 RNAct 1 RefSeq 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 UCSC 1 VEuPathDB 1 eggNOG 1 neXtProt 1

Citations:

PubMed ID: 16641997

Title: The DNA sequence, annotation and analysis of human chromosome 3.

PubMed ID: 16641997

DOI: 10.1038/nature04728

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

Sequence Information:

  • Length: 97
  • Mass: 10821
  • Checksum: 9DEC4480C8E96D7D
  • Sequence:
    • MKGICSDAIL VLATSMWMAF AIDFPLPMAS ERGQLDKTIV ECLKNVNKCW FLSYIKPSEP 
ICGSDQVTYS SDCHLCSKIL FEGLNITKLY DGQCENS