Details for: DIABLO

Gene ID: 56616

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: DIABLO

Ensembl ID: ENSG00000184047

Description: diablo IAP-binding mitochondrial protein

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • radial glial cell CL0000681
    CSI 3.12
    rCSI 4.34%
    PRS 93.79
  • plasmablast CL0000980
    CSI 3.04
    rCSI 2.39%
    PRS 95.85
  • alpha-beta T cell CL0000789
    CSI 2.89
    rCSI 3.38%
    PRS 98.55
  • respiratory basal cell CL0002633
    CSI 2.88
    rCSI 2.98%
    PRS 95.97
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 2.26
    rCSI 2.61%
    PRS 89.54
  • ependymal cell CL0000065
    CSI 2.21
    rCSI 4.49%
    PRS 81.55
  • fraction A pre-pro B cell CL0002045
    CSI 2.07
    rCSI 2.37%
    PRS 96.86
  • neuroblast (sensu Vertebrata) CL0000031
    CSI 1.95
    rCSI 2.5%
    PRS 92.39
  • peripheral nervous system neuron CL2000032
    CSI 1.73
    rCSI 2.36%
    PRS 90.66
  • astrocyte of the cerebral cortex CL0002605
    CSI 1.67
    rCSI 3.75%
    PRS 87.01
  • glioblast CL0000030
    CSI 1.63
    rCSI 2.6%
    PRS 89.58
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.5
    rCSI 2.41%
    PRS 87.72
  • neural progenitor cell CL0011020
    CSI 1
    rCSI 4.39%
    PRS 86.55
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 0.8
    rCSI 1.94%
    PRS 84.96
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.77
    rCSI 2.4%
    PRS 87.76
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 0.71
    rCSI 2.68%
    PRS 86.93
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 0.4
    rCSI 2.34%
    PRS 87.23

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)

Loading network (please wait)...

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 [DIABLO](/details-gene/56616), or diablo IAP-binding mitochondrial protein, is a central pro-apoptotic regulator encoded on chromosome 12. This protein is synthesized and localized to the mitochondrial intermembrane space. Upon induction of apoptosis, [DIABLO](/details-gene/56616) is released into the cytosol where it promotes programmed cell death by binding to and neutralizing members of the Inhibitor of Apoptosis Protein (IAP) family [Link](https://doi.org/10.1016/s0092-8674(00)00008-8). This action liberates caspases from IAP-mediated inhibition, thereby enabling the execution phase of apoptosis. Expression data indicates that **'Overall'**, [DIABLO](/details-gene/56616) is a significant gene in diverse and highly regulated cell populations, including neural progenitors like `[radial glial cell](/details-cell/CL0000681)`, immune cells such as `[plasmablast](/details-cell/CL0000980)` and `[alpha-beta T cell](/details-cell/CL0000789)`, and tissue progenitor cells like `[respiratory basal cell](/details-cell/CL0002633)`. This pattern suggests its fundamental role in apoptosis is critical for nervous system development, immune homeostasis, and tissue maintenance. ## Cellular Roles and Expression Landscape The expression profile of [DIABLO](/details-gene/56616) highlights its importance in cellular contexts requiring stringent control over cell survival and death. Its high significance in a range of neural cell types—including `[radial glial cell](/details-cell/CL0000681)` (CSI: 3.12), `[neuroblast (sensu Vertebrata)](/details-cell/CL0000031)` (CSI: 1.95), and `[ependymal cell](/details-cell/CL0000065)` (CSI: 2.21)—underscores its likely involvement in the extensive programmed cell death that occurs during the development and sculpting of the central nervous system. In the immune system, [DIABLO](/details-gene/56616) is a key gene in cells undergoing differentiation and clonal selection. Its high CSI in `[plasmablast](/details-cell/CL0000980)` (CSI: 3.04), `[alpha-beta T cell](/details-cell/CL0000789)` (CSI: 2.89), and `[fraction A pre-pro B cell](/details-cell/CL0002045)` (CSI: 2.07) is consistent with a role in eliminating self-reactive lymphocytes and shaping the mature immune repertoire. Furthermore, its prominence in progenitor populations like `[respiratory basal cell](/details-cell/CL0002633)` suggests it is a critical factor in maintaining tissue homeostasis in environments with high cellular turnover, ensuring damaged or excess cells are efficiently removed. The broad expression across these functionally distinct, yet highly regulated, cell types points to [DIABLO](/details-gene/56616) as a fundamental executor of programmed cell death essential for organismal development and health. ## Pathways and Molecular Function Functional annotations confirm that [DIABLO](/details-gene/56616) is a core component of the apoptotic machinery. Its molecular function is centered on its ability to bind IAP proteins, a mechanism detailed in the Reactome pathway `[Smac (diablo) binds to iaps](/details-cell/R-HSA-111463)`. This interaction directly leads to the `[Smac(diablo)-mediated dissociation of iap:caspase complexes](/details-cell/R-HSA-111464)`, thereby promoting `[Activation of cysteine-type endopeptidase activity involved in apoptotic process](/details-cell/GO:0006919)`. The protein acts as a crucial link in the `[Intrinsic pathway for apoptosis](/details-cell/R-HSA-109606)`, initiating its function following `[Release of apoptotic factors from the mitochondria](/details-cell/R-HSA-111457)`. This is often triggered by cellular stress and leads to the formation of the apoptosome. The high expression of [DIABLO](/details-gene/56616) in neural lineages is functionally corroborated by its annotation in the `[Neuron apoptotic process](/details-cell/GO:0051402)`. Its involvement in both the `[Intrinsic apoptotic signaling pathway](/details-cell/GO:0097193)` and the `[Extrinsic apoptotic signaling pathway via death domain receptors](/details-cell/GO:0008625)` suggests it serves as a convergence point, ensuring robust execution of the cell death program regardless of the initiating signal. ## Research Directions The role of [DIABLO](/details-gene/56616) as a central pro-apoptotic factor makes its dysregulation a plausible mechanism in numerous pathologies, particularly cancer and neurodegenerative diseases. Based on its expression profile and known function, several testable hypotheses can be proposed. 1. **Role in Neurodevelopmental and Neurodegenerative Disorders:** Given the high significance of [DIABLO](/details-gene/56616) in `[radial glial cell](/details-cell/CL0000681)` and various `[neuroblast](/details-cell/CL0000338)` populations, it is hypothesized that germline mutations or altered expression of [DIABLO](/details-gene/56616) could disrupt the precise balance of apoptosis required for proper brain development, potentially contributing to neurodevelopmental disorders. Conversely, aberrant activation or upregulation of [DIABLO](/details-gene/56616) in mature neurons may sensitize them to stress, contributing to the neuronal loss seen in neurodegenerative diseases like Alzheimer's or Parkinson's disease. 2. **Mechanism of Tumor Immune Evasion:** The high CSI of [DIABLO](/details-gene/56616) in `[alpha-beta T cell](/details-cell/CL0000789)` suggests it is important for T-cell function. It is hypothesized that cancer cells may develop resistance to cytotoxic T-cell-mediated killing by interfering with the [DIABLO](/details-gene/56616) pathway. This could occur through direct downregulation of [DIABLO](/details-gene/56616) in the tumor cell, making it resistant to granzyme B-induced apoptosis, or by secreting factors that suppress [DIABLO](/details-gene/56616) expression in infiltrating immune cells. A key experiment to test the role of [DIABLO](/details-gene/56616) in mediating chemoresistance could be performed. Using CRISPR-Cas9, [DIABLO](/details-gene/56616) could be knocked out in cancer cell lines where it is endogenously expressed (e.g., neuroblastoma or lymphoid leukemia lines, reflecting the expression data). These knockout cells, alongside isogenic wild-type controls, would be treated with a dose-response of chemotherapeutic agents known to induce intrinsic apoptosis (e.g., etoposide). Cell viability would be measured via MTT assay, and apoptosis rates would be quantified using flow cytometry for Annexin V staining. A significant increase in the IC50 value and a reduction in apoptotic cells in the [DIABLO](/details-gene/56616)-knockout lines would provide direct evidence of its role in chemosensitivity. From a therapeutic perspective, [DIABLO](/details-gene/56616) is a compelling target. However, the strategy would not be inhibition, but rather **functional mimicry or activation**. Because it antagonizes anti-apoptotic IAP proteins, developing small molecules that mimic the IAP-binding motif of [DIABLO](/details-gene/56616) (known as "Smac mimetics") is a well-established strategy to induce apoptosis in cancer cells. These compounds are designed to overcome the apoptotic blockade that is a hallmark of cancer, potentially re-sensitizing resistant tumors to conventional therapies.

Genular Protein ID: 3895163525

Symbol: DBLOH_HUMAN

Name: Diablo IAP-binding mitochondrial protein, cleaved form

UniProtKB Accession Codes:

Q9NR28 B2RDQ0 Q6W3F3 Q96LV0 Q9BT11 Q9HAV6

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CTD 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 DrugBank 1 EMBL 9 EMDB 4 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 13 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 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 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 16 PDBsum 16 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 Pumba 1 RNAct 1 Reactome 5 RefSeq 6 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TopDownProteomics 3 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10929711

Title: Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.

PubMed ID: 10929711

DOI: 10.1016/s0092-8674(00)00008-8

PubMed ID: 10950947

Title: Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway.

PubMed ID: 10950947

DOI: 10.1074/jbc.c000533200

PubMed ID: 14523016

Title: Smac3, a novel Smac/DIABLO splicing variant, attenuates the stability and apoptosis-inhibiting activity of X-linked inhibitor of apoptosis protein.

PubMed ID: 14523016

DOI: 10.1074/jbc.m308036200

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16541075

Title: The finished DNA sequence of human chromosome 12.

PubMed ID: 16541075

DOI: 10.1038/nature04569

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: 15200957

Title: Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase.

PubMed ID: 15200957

DOI: 10.1016/j.molcel.2004.05.018

PubMed ID: 16729033

Title: Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway.

PubMed ID: 16729033

DOI: 10.1038/sj.cdd.4401959

PubMed ID: 21695558

Title: ARTS binds to a distinct domain in XIAP-BIR3 and promotes apoptosis by a mechanism that is different from other IAP-antagonists.

PubMed ID: 21695558

DOI: 10.1007/s10495-011-0622-0

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 21536684

Title: Survivin monomer plays an essential role in apoptosis regulation.

PubMed ID: 21536684

DOI: 10.1074/jbc.m111.237586

PubMed ID: 23479728

Title: Identification of a novel anti-apoptotic E3 ubiquitin ligase that ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, and ARTS.

PubMed ID: 23479728

DOI: 10.1074/jbc.m112.436113

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 25944712

Title: N-terminome analysis of the human mitochondrial proteome.

PubMed ID: 25944712

DOI: 10.1002/pmic.201400617

PubMed ID: 28288130

Title: PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis.

PubMed ID: 28288130

DOI: 10.1038/ncb3488

PubMed ID: 10972280

Title: Structural and biochemical basis of apoptotic activation by Smac/DIABLO.

PubMed ID: 10972280

DOI: 10.1038/35022514

PubMed ID: 11140637

Title: Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain.

PubMed ID: 11140637

DOI: 10.1038/35050006

PubMed ID: 19153467

Title: The structure of the BIR3 domain of cIAP1 in complex with the N-terminal peptides of SMAC and caspase-9.

PubMed ID: 19153467

DOI: 10.1107/s0907444908039243

PubMed ID: 36758104

Title: Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases.

PubMed ID: 36758104

DOI: 10.1126/science.ade5750

PubMed ID: 36758106

Title: Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6.

PubMed ID: 36758106

DOI: 10.1126/science.ade8840

PubMed ID: 36758105

Title: Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex.

PubMed ID: 36758105

DOI: 10.1126/science.ade8873

PubMed ID: 21722859

Title: Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64.

PubMed ID: 21722859

DOI: 10.1016/j.ajhg.2011.05.027

Sequence Information:

  • Length: 239
  • Mass: 27131
  • Checksum: 70C2AE0DC654D031
  • Sequence:
    • MAALKSWLSR SVTSFFRYRQ CLCVPVVANF KKRCFSELIR PWHKTVTIGF GVTLCAVPIA 
QKSEPHSLSS EALMRRAVSL VTDSTSTFLS QTTYALIEAI TEYTKAVYTL TSLYRQYTSL 
LGKMNSEEED EVWQVIIGAR AEMTSKHQEY LKLETTWMTA VGLSEMAAEA AYQTGADQAS 
ITARNHIQLV KLQVEEVHQL SRKAETKLAE AQIEELRQKT QEEGEERAES EQEAYLRED

Genular Protein ID: 3439419326

Symbol: Q502X2_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q502X2

Database IDs:

ARBA 6 AlphaFoldDB 1 BioGRID-ORCS 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 6 GO 3 Gene3D 1 InterPro 2 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 Pfam 1 RefSeq 3 SAM 1 SMR 1 SUPFAM 1

Citations:

PubMed ID: 11181995

Title: The sequence of the human genome.

PubMed ID: 11181995

DOI: 10.1126/science.1058040

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: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

Sequence Information:

  • Length: 186
  • Mass: 21233
  • Checksum: FF567F7827AB6108
  • Sequence:
    • MKSDFYFQKS EPHSLSSEAL MRRAVSLVTD STSTFLSQTT YALIEAITEY TKAVYTLTSL 
YRQYTSLLGK MNSEEEDEVW QVIIGARAEM TSKHQEYLKL ETTWMTAVGL SEMAAEAAYQ 
TGADQASITA RNHIQLVKLQ VEEVHQLSRK AETKLAEAQI EELRQKTQEE GEERAESEQE 
AYLRED

Genular Protein ID: 1993431731

Symbol: K7X1S0_HUMAN

Name: N/A

UniProtKB Accession Codes:

K7X1S0

Database IDs:

ARBA 6 AlphaFoldDB 1 BioGRID-ORCS 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 2 GO 3 Gene3D 1 InterPro 2 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PeptideAtlas 1 Pfam 1 RefSeq 1 SAM 1 SUPFAM 1

Sequence Information:

  • Length: 142
  • Mass: 16314
  • Checksum: 3799FFEBD82DED75
  • Sequence:
    • MKSDFYFQAV YTLTSLYRQY TSLLGKMNSE EEDEVWQVII GARAEMTSKH QEYLKLETTW 
MTAVGLSEMA AEAAYQTGAD QASITARNHI QLVKLQVEEV HQLSRKAETK LAEAQIEELR 
QKTQGEGEER AESEQEAYLR ED

Genular Protein ID: 1576175559

Symbol: A0A0S2Z5P6_HUMAN

Name: N/A

UniProtKB Accession Codes:

A0A0S2Z5P6

Database IDs:

ARBA 6 AlphaFoldDB 1 Antibodypedia 1 BioGRID-ORCS 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 2 ExpressionAtlas 1 GO 4 Gene3D 1 InterPro 2 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 Pfam 1 RefSeq 1 SAM 2 SMR 1 SUPFAM 1 VEuPathDB 1

Citations:

PubMed ID: 26871637

Title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.

PubMed ID: 26871637

DOI: 10.1016/j.cell.2016.01.029

Sequence Information:

  • Length: 195
  • Mass: 22284
  • Checksum: B344087CF2A87C05
  • Sequence:
    • MAALKSWLSR SVTSFFRYRQ CLCVPVVANF KKRCFSELIR PWHKTVTIGF GVTLCAVPIA 
QAVYTLTSLY RQYTSLLGKM NSEEEDEVWQ VIIGARAEMT SKHQEYLKLE TTWMTAVGLS 
EMAAEAAYQT GADQASITAR NHIQLVKLQV EEVHQLSRKA ETKLAEAQIE ELRQKTQEEG 
EERAESEQEA YLRED