Details for: CASP5

Gene ID: 838

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: CASP5

Ensembl ID: ENSG00000137757

Description: caspase 5

Cell Significance Landscape

Associated with

Significant Cells

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

  • colon epithelial cell CL0011108
    CSI 5.81
    rCSI 6.09%
    PRS 88.11
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 3.61
    rCSI 2.78%
    PRS 93.26
  • basal cell of epidermis CL0002187
    CSI 2.67
    rCSI 4.74%
    PRS 61.78
  • melanocyte of skin CL1000458
    CSI 0.98
    rCSI 1.33%
    PRS 61.33
  • suprabasal keratinocyte CL4033013
    CSI 0.72
    rCSI 1.18%
    PRS 61.42

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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  • 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 [CASP5](/details-gene/838) (caspase 5) is a protein-coding gene located on chromosome 11 that encodes a member of the caspase family of cysteine proteases. Functionally, [CASP5](/details-gene/838) is a critical component of the innate immune system, where it acts as an inflammatory caspase. It is an integral part of inflammasome complexes, protein platforms that sense pathogenic or endogenous danger signals. Upon activation, [CASP5](/details-gene/838) initiates a pro-inflammatory form of programmed cell death known as pyroptosis, contributing to pathogen clearance and the inflammatory response. Expression data indicate its highest significance is in barrier epithelial cells, particularly [colon epithelial cell](/details-cell/CL0011108), and in pro-inflammatory immune cells such as the [CD14-low, CD16-positive monocyte](/details-cell/CL0002396), highlighting its role as a frontline sensor in mucosal and systemic immunity. Its dysregulation is associated with inflammatory disorders, as noted in its OMIM entry ([602665](https://omim.org/entry/602665)). ## Cellular Roles and Expression Landscape The expression profile of [CASP5](/details-gene/838) strongly suggests a primary role in innate immune surveillance at barrier tissues and within specific immune cell populations. **Overall**, the gene shows its most significant expression (CSI: 5.81) in the [colon epithelial cell](/details-cell/CL0011108). This points to a crucial function in maintaining gut homeostasis and responding to enteric pathogens by triggering localized inflammation and cell death to prevent microbial invasion. This is complemented by its high significance in epithelial cells of the skin, including [basal cell of epidermis](/details-cell/CL0002187) (CSI: 2.67) and [suprabasal keratinocyte](/details-cell/CL4033013) (CSI: 0.72), underscoring a conserved role in protecting the body's primary external barriers. In addition to its role in epithelial tissues, [CASP5](/details-gene/838) is also a significant marker for the [CD14-low, CD16-positive monocyte](/details-cell/CL0002396) (CSI: 3.61). This "non-classical" monocyte subset is known for its patrolling function and potent pro-inflammatory responses, suggesting that [CASP5](/details-gene/838) is a key effector molecule for this cell type during systemic immune surveillance and in response to infection. ## Pathways and Molecular Function [CASP5](/details-gene/838) functions as a protease with a specific [cysteine-type endopeptidase activity](/details-go/GO0004197). This enzymatic activity is central to its role in the [positive regulation of inflammatory response](/details-go/GO0050729). Within the cell, [CASP5](/details-gene/838) is localized to the [cytosol](/details-go/GO0005829), where it is recruited to multi-protein platforms such as the [Nlrp1 inflammasome complex](/details-go/GO0072558). Along with its close homolog Caspase-4, [CASP5](/details-gene/838) is a key sensor of the non-canonical inflammasome pathway, which directly recognizes intracellular lipopolysaccharide (LPS) from Gram-negative bacteria. This activation triggers a cascade leading to [Pyroptosis](/details-pathway/R-HSA-5620971), a lytic form of [programmed cell death](/details-pathway/R-HSA-5357801). A key step in this process is the [CASP5](/details-gene/838)-mediated cleavage of Gasdermin D, which forms pores in the plasma membrane, leading to cell lysis and the release of inflammatory mediators ([Link](https://doi.org/10.15252/embj.201798321)). Recent evidence also highlights a role for this pathway in the maturation of key cytokines like IL-18 ([Link](https://doi.org/10.1038/s41586-023-06742-w)). Its involvement in proteolysis ([GO:0006508](https://www.ebi.ac.uk/QuickGO/term/GO:0006508)) and the [apoptotic process](/details-go/GO0006915) further solidifies its identity as a crucial regulator of cellular fate in response to stress and infection. ## Research Directions The specific expression pattern and pro-inflammatory function of [CASP5](/details-gene/838) suggest several avenues for future research, particularly concerning its role in disease. **Proposed Hypotheses:** 1. Given its exceptionally high significance in [colon epithelial cell](/details-cell/CL0011108), the dysregulation of [CASP5](/details-gene/838)-mediated pyroptosis in these cells is a key initiating event in inflammatory bowel disease (IBD). Hyper-activation may lead to excessive epithelial cell death, barrier disruption, and chronic inflammation. 2. The high expression of [CASP5](/details-gene/838) in [CD14-low, CD16-positive monocyte](/details-cell/CL0002396) suggests that it is a critical driver of the hyper-inflammatory state observed in sepsis. Activation of [CASP5](/details-gene/838) in this cell type upon systemic exposure to bacterial LPS may contribute significantly to the cytokine storm and endothelial damage characteristic of septic shock. **Experimental Approach:** To test the role of [CASP5](/details-gene/838) in intestinal barrier defense (Hypothesis 1), one could generate [CASP5](/details-gene/838) knockout human colon organoids using CRISPR-Cas9. These organoids could then be challenged with an enteric pathogen like *Salmonella Typhimurium* or its purified LPS. The impact on cell death (quantifying pyroptosis via LDH release and GSDMD cleavage), barrier integrity (measuring transepithelial electrical resistance), and the release of key cytokines (IL-1beta, IL-18) could be precisely measured and compared to isogenic wild-type controls. **Therapeutic Potential:** Given its role as a key driver of pro-inflammatory pyroptosis, [CASP5](/details-gene/838) represents a promising therapeutic target for **inhibition** in diseases characterized by excessive inflammation, such as IBD, sepsis, or certain autoinflammatory conditions. As an intracellular protease, it would likely be targeted by cell-permeable small molecule inhibitors rather than antibodies. A significant challenge will be to achieve targeted drug delivery to specific inflamed tissues or cell types, as systemic inhibition of [CASP5](/details-gene/838) could compromise the host's ability to clear bacterial infections, potentially increasing susceptibility to pathogens.

Genular Protein ID: 3590721377

Symbol: CASP5_HUMAN

Name: Caspase-5 subunit p20

UniProtKB Accession Codes:

P51878 B4DKP5 Q0QVY7 Q0QVY8 Q0QVZ0 Q0QVZ1 Q0QVZ2 Q14DD6 Q1HBJ3 Q6DJV7

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 4 CDD 1 CORUM 1 CTD 1 ChEMBL 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 13 Ensembl 7 ExpressionAtlas 1 GO 12 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 9 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PIR 1 PIRSF 1 PRINTS 1 PRO 1 PROSITE 5 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 6 RNAct 1 Reactome 1 RefSeq 4 SABIO-RK 1 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 16893518

Title: Identification of a novel exon encoding the amino-terminus of the predominant caspase-5 variants.

PubMed ID: 16893518

DOI: 10.1016/j.bbrc.2006.07.104

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16554811

Title: Human chromosome 11 DNA sequence and analysis including novel gene identification.

PubMed ID: 16554811

DOI: 10.1038/nature04632

PubMed ID: 7797592

Title: Molecular cloning and pro-apoptotic activity of ICErelII and ICErelIII, members of the ICE/CED-3 family of cysteine proteases.

PubMed ID: 7797592

DOI: 10.1074/jbc.270.26.15870

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: 8617266

Title: Identification of a cysteine protease closely related to interleukin-1 beta-converting enzyme.

PubMed ID: 8617266

DOI: 10.1111/j.1432-1033.1996.t01-1-00207.x

PubMed ID: 17431422

Title: The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing.

PubMed ID: 17431422

DOI: 10.1038/sj.cdd.4402142

PubMed ID: 29898893

Title: Mechanism of membrane pore formation by human gasdermin-D.

PubMed ID: 29898893

DOI: 10.15252/embj.201798321

PubMed ID: 28314590

Title: Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to regulate responses to DNA virus infection.

PubMed ID: 28314590

DOI: 10.1016/j.immuni.2017.02.011

PubMed ID: 30692621

Title: SERPINB1-mediated checkpoint of inflammatory caspase activation.

PubMed ID: 30692621

DOI: 10.1038/s41590-018-0303-z

PubMed ID: 37993714

Title: Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome.

PubMed ID: 37993714

DOI: 10.1038/s41586-023-06742-w

Sequence Information:

  • Length: 434
  • Mass: 49736
  • Checksum: C5257C2BF15EB6D5
  • Sequence:
    • MAEDSGKKKR RKNFEAMFKG ILQSGLDNFV INHMLKNNVA GQTSIQTLVP NTDQKSTSVK 
KDNHKKKTVK MLEYLGKDVL HGVFNYLAKH DVLTLKEEEK KKYYDTKIED KALILVDSLR 
KNRVAHQMFT QTLLNMDQKI TSVKPLLQIE AGPPESAEST NILKLCPREE FLRLCKKNHD 
EIYPIKKRED RRRLALIICN TKFDHLPARN GAHYDIVGMK RLLQGLGYTV VDEKNLTARD 
MESVLRAFAA RPEHKSSDST FLVLMSHGIL EGICGTAHKK KKPDVLLYDT IFQIFNNRNC 
LSLKDKPKVI IVQACRGEKH GELWVRDSPA SLALISSQSS ENLEADSVCK IHEEKDFIAF 
CSSTPHNVSW RDRTRGSIFI TELITCFQKY SCCCHLMEIF RKVQKSFEVP QAKAQMPTIE 
RATLTRDFYL FPGN