DIABLO

Summary

DIABLO (diablo IAP-binding mitochondrial protein, HGNC:21528) is a protein-coding gene on chromosome 12q24.31, encoding Diablo IAP-binding mitochondrial protein (Q9NR28). Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway.

This gene encodes an inhibitor of apoptosis protein (IAP)-binding protein. The encoded mitochondrial protein enters the cytosol when cells undergo apoptosis, and allows activation of caspases by binding to inhibitor of apoptosis proteins. Overexpression of the encoded protein sensitizes tumor cells to apoptosis. A mutation in this gene is associated with young-adult onset of nonsyndromic deafness-64. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 56616 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant nonsyndromic hearing loss (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 128 total — 2 likely-pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_001371333

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21528
Approved symbol	DIABLO
Name	diablo IAP-binding mitochondrial protein
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	SMAC, DIABLO-S, FLJ25049, FLJ10537, DFNA64
Ensembl gene	ENSG00000184047
Ensembl biotype	protein_coding
OMIM	605219
Entrez	56616

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 9 protein_coding, 5 nonsense_mediated_decay, 5 retained_intron

ENST00000267169, ENST00000342392, ENST00000353548, ENST00000439489, ENST00000446652, ENST00000464942, ENST00000474004, ENST00000489781, ENST00000540535, ENST00000541273, ENST00000541656, ENST00000642640, ENST00000644227, ENST00000644509, ENST00000645569, ENST00000867260, ENST00000867261, ENST00000867262, ENST00000920225

RefSeq mRNA: 6 — MANE Select: NM_001371333 NM_001278303, NM_001278304, NM_001278342, NM_001371333, NM_019887, NM_138930

CCDS: CCDS9228, CCDS9229

Canonical transcript exons

ENST00000464942 — 6 exons

Exon	Start	End
ENSE00003688078	122225965	122226052
ENSE00003855046	122218266	122218397
ENSE00003863155	122207668	122208577
ENSE00003871435	122224512	122224644
ENSE00003900616	122216488	122216584
ENSE00003901373	122216759	122216869

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 96.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.8326 / max 1106.1025, expressed in 1824 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133796	51.1413	1824
133794	2.9359	1409
133795	0.6489	304
133797	0.0812	32
133798	0.0253	5

Top tissues by expression

142 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	96.49	gold quality
left testis	UBERON:0004533	96.39	gold quality
islet of Langerhans	UBERON:0000006	95.98	gold quality
testis	UBERON:0000473	95.83	gold quality
adenohypophysis	UBERON:0002196	94.45	gold quality
ganglionic eminence	UBERON:0004023	94.44	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.34	gold quality
hypothalamus	UBERON:0001898	94.32	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.26	gold quality
substantia nigra	UBERON:0002038	94.20	gold quality
pituitary gland	UBERON:0000007	94.01	gold quality
ventricular zone	UBERON:0003053	93.89	gold quality
corpus callosum	UBERON:0002336	93.70	gold quality
adrenal tissue	UBERON:0018303	93.68	gold quality
cortical plate	UBERON:0005343	93.54	gold quality
mucosa of transverse colon	UBERON:0004991	93.47	gold quality
placenta	UBERON:0001987	93.44	gold quality
amygdala	UBERON:0001876	93.01	gold quality
putamen	UBERON:0001874	92.98	gold quality
temporal lobe	UBERON:0001871	92.94	gold quality
anterior cingulate cortex	UBERON:0009835	92.78	gold quality
pancreas	UBERON:0001264	92.72	gold quality
adult mammalian kidney	UBERON:0000082	92.64	gold quality
caudate nucleus	UBERON:0001873	92.58	gold quality
nucleus accumbens	UBERON:0001882	92.58	gold quality
Ammon’s horn	UBERON:0001954	92.43	gold quality
brain	UBERON:0000955	92.39	gold quality
prefrontal cortex	UBERON:0000451	92.37	gold quality
rectum	UBERON:0001052	92.31	gold quality
endometrium	UBERON:0001295	92.25	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.91

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, E2F1, PAWR

miRNA regulators (miRDB)

28 targeting DIABLO, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-1294	98.91	69.26	1030
HSA-MIR-9986	98.91	69.28	1024
HSA-MIR-6838-3P	98.40	65.88	559
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-6737-5P	97.75	66.54	1044
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-3976	96.67	67.79	1187
HSA-MIR-4750-3P	96.65	64.38	512
HSA-MIR-487B-3P	88.08	68.35	83

Literature-anchored findings (GeneRIF, showing 40)

• prevention of mitochondrial release by bcl-2 and bcl-xL inhibition of CD95-mediated apoptosis (PMID:11801595)
• potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis (PMID:11964312)
• Data show that transfer of the gene encoding Smac sensitized tumor and malignant glioma cells for apoptosis, and that Smac peptides enhanced the antitumor activity of Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). (PMID:12118245)
• SMAC protein is regulated by XIAP and degraded by proteasome (PMID:12121969)
• Smac-penetratin fusion peptide crossed the cellular membrane, bound XIAP and cIAP1, displaced caspase-3 from cytoplasmic aggregates, and enhanced drug-induced caspase action in situ (PMID:12218061)
• translocation of Smac along with cytochrome c and other mitochondrial pro-apoptotic proteins represent important regulatory checkpoints for mitochondria-mediated apoptosis (PMID:12364342)
• Reovirus-induced apoptosis requires mitochondrial release of Smac/DIABLO (PMID:12388702)
• Cellular inhibitors of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO. (PMID:12525502)
• TRAF2, TRAF3, cIAP1, Smac, and lymphotoxin beta receptor associate and are involved in apoptosis (PMID:12571250)
• role in leukemic cell apoptosis (PMID:12642862)
• Smac is released during stress-induced apoptosis in multiple myeloma cells (PMID:12665525)
• Transfection of ovarian carcinoma cells with Smac causes apoptosis. Smac-induced apoptosis proceeds via a pathway mediated by caspase-9 and is inhibited by XIAP protein. (PMID:12749848)
• The sustained release of Smac/DIABLO from mitochondria is an important event for the onset of apoptosis in keratinocytes exposed to UVB irradiation. In human keratinocytes UVB irradiation at 500 J/m(2), but not at 150 J/m(2), induces apoptosis. (PMID:12766489)
• Blocking Hsp27 by an antisense strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac (PMID:12855565)
• The duration of Smac release was greater than that of cytochrome c. However, there was no difference in the time to the onset of release, and both cytochrome c and Smac release coincided with mitochondrial membrane potential depolarization. (PMID:12975347)
• role in relieving XIAP-mediated caspase inhibition (PMID:14512414)
• Smac3 is a novel Smac/DIABLO splicing variant and attenuates the stability and apoptosis-inhibiting activity of XIAP (PMID:14523016)
• Data show that the mechanism by which fibroblast growth factor 2 protects small cell lung cancer cells from etoposide-induced cell death involves inhibition of Smac release but not of cytochrome c release. (PMID:14560006)
• compared Grim and Diablo. Although they have the same IAP binding specificity, only Grim promoted XIAP ubiquitination and degradation. (PMID:14570909)
• Smac may serve as a key molecule in vivo to selectively reduce the protein level of c-IAPs through the ubiquitin/proteasome pathway (PMID:14960576)
• Smac deficiency may be compensated for by action of redundant determinants to kill cancer cells. Thus, translocation of endogenous Smac into cytosol does not play a critical role in cell death of human lung carcinoma after etoposide treatment. (PMID:15242764)
• Apollon binds to, ubiquitinates and facilitates proteasomal degradation of SMAC and caspase-9, results suggesting that Apollon has an essential function in preventing SMAC-induced apoptosis (PMID:15300255)
• electrostatic interations do not hold Smac/DIABLO to mitochondrial membranes (PMID:15537572)
• Expression of Smac/DIABLO can stimulate the intrinsic pathway of apoptosis in ovarian carcinoma without damaging normal ovarian tissue and therefore has therapeutic potential. (PMID:15541727)
• in HeLa cells, both Smac and Cyt-c are released from mitochondria during UV-induced apoptosis through the same permeability transition mechanism triggered by aggregation of Bax (PMID:15843890)
• Data show that Transfection and expression of human Smac gene could significantly induce apoptosis of human Burkitt’s lymphoma Raji cells. (PMID:16083549)
• A novel function of SMAC, inhibition of clonogenic tumor growth, contributes to its antitumor activity. (PMID:16091752)
• a single cIAP can direct its E3 ligase activity toward different substrates and can alter the cellular functions of different protein targets, including TRAF2 and SMAC, in accordance with differences in the specificity of individual BIR domains (PMID:16282325)
• SMAC/DIABLO mutations in gastric and colorectal carcinomas suggest their role in the development of these tumors. (PMID:16484020)
• Apoptosis induced by bufalin is related to mitochondrial release of Smac/DIABLO. (PMID:16732934)
• In HL cells, grzB-induced mitochondrial release of proapoptotic Smac is blocked, which results in complete abrogation of cytotoxicity mediated by CTLs. (PMID:16868249)
• Smac/DIABLO is differentially expressed in various types of B-cell non-Hodgkin lymphomas and Hodgkin lymphomas, suggesting that apoptotic mechanisms are differentially involved in the pathogenesis of these diseases (PMID:16949641)
• This suggests that the balance between cellular Smac/DIABLO and Survivin levels could be critical for cellular destiny in taxane-treated cancer cells. (PMID:17045968)
• These data suggest that Rv1818c-induced apoptotic signaling is likely regulated in part by the Smac-dependent activation of caspases in T cells. (PMID:17223373)
• Second mitochondria-derived activator of caspase (SMAC)/Diablo participates in a feedback amplification loop to promote cytochrome c release and other mitochondrial events in apoptosis. (PMID:17237824)
• TRAF3 interacts with Smac/DIABLO via TRAF domain, leading to an increased proapoptotic effect of Smac/DIABLO in cytoplasm. (PMID:17277885)
• Our findings indicate that the use of small molecule Smac mimic, when combined with an apoptotic trigger, may have therapeutic potential for the treatment of NSCLC. (PMID:17291493)
• These results show that cyclic AMP is an important modulator of the apoptotic threshold in cancer cell by means of regulating Smac/DIABLO expression. (PMID:17320350)
• An obligatory role for Smac/DIABLO in these tumor cells during several pathways of apoptosis induction. (PMID:17440818)
• Results indicate that the suppression of IAPs expression by Smac/DIABLO shortly after proapoptotic stimulation might play a role in the mechanisms of apoptotic induction. (PMID:17521628)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	diablob	ENSDARG00000014956
danio_rerio	diabloa	ENSDARG00000104172
mus_musculus	Diablo	ENSMUSG00000029433
rattus_norvegicus	Diablol1	ENSRNOG00000008548
rattus_norvegicus	Diablo	ENSRNOG00000029197

Protein

Protein identifiers

Diablo IAP-binding mitochondrial protein — Q9NR28 (reviewed: Q9NR28)

Alternative names: Diablo homolog, mitochondrial, Direct IAP-binding protein with low pI, Second mitochondria-derived activator of caspases

All UniProt accessions (10): A0A0S2Z5P6, A0A0S2Z5U7, A0A2R8Y5H2, A0A2U3TZH2, Q9NR28, F5GX50, F5GXT8, F5GYH3, H7BZK7, H7BZQ7

UniProt curated annotations — full annotation on UniProt →

Function. Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway. Acts by opposing the inhibitory activity of inhibitor of apoptosis proteins (IAP). Inhibits the activity of BIRC6/BRUCE by inhibiting its binding to caspases. Attenuates the stability and apoptosis-inhibiting activity of XIAP/BIRC4 by promoting XIAP/BIRC4 ubiquitination and degradation through the ubiquitin-proteasome pathway. Also disrupts XIAP/BIRC4 interacting with processed caspase-9 and promotes caspase-3 activation. Defective in the capacity to down-regulate the XIAP/BIRC4 abundance.

Subunit / interactions. Homodimer. Interacts with BIRC2/c-IAP1 (via BIR3 domain). Interacts with BIRC6/BRUCE; inhibits BIRC6 activity. Interacts with BIRC7/livin. Interacts with XIAP/BIRC4 (via BIR3 domain). Interacts with the monomeric and dimeric form of BIRC5/survivin. Interacts with AREL1 (via HECT domain); in the cytoplasm following induction of apoptosis. Interacts with BEX3.

Subcellular location. Mitochondrion. Cytoplasm. Cytosol.

Tissue specificity. Ubiquitously expressed with highest expression in testis. Expression is also high in heart, liver, kidney, spleen, prostate and ovary. Low in brain, lung, thymus and peripheral blood leukocytes. Isoform 3 is ubiquitously expressed.

Post-translational modifications. Ubiquitinated by BIRC7/livin. Ubiquitinated by BIRC6. The precursor form is proteolytically cleaved by mitochondrial processing peptidase MPP to remove the transit peptide and produce an intermediate form. This is then processed by PARL to produce the mature cleaved form which is released from mitochondria into the cytosol in apoptotic cells.

Disease relevance. Deafness, autosomal dominant, 64 (DFNA64) [MIM:614152] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The mature N-terminus mediates interaction with XIAP/BIRC4.

Similarity. Belongs to the Smac/DIABLO protein family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NR28-1	1	yes
Q9NR28-2	2, Diablo-S
Q9NR28-3	3, SMAC3

RefSeq proteins (5): NP_001265232, NP_001265271, NP_001358262, NP_063940, NP_620308 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009062	Smac/DIABLO-like_sf	Homologous_superfamily
IPR015142	Smac_DIABLO	Family

Pfam: PF09057

UniProt features (19 total): sequence conflict 3, helix 3, chain 2, mutagenesis site 2, strand 2, splice variant 2, transit peptide 1, region of interest 1, short sequence motif 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
1TW6	X-RAY DIFFRACTION	1.71
4TX5	X-RAY DIFFRACTION	1.8
1G73	X-RAY DIFFRACTION	2
1FEW	X-RAY DIFFRACTION	2.2
1XB0	X-RAY DIFFRACTION	2.2
1OXQ	X-RAY DIFFRACTION	2.3
3D9U	X-RAY DIFFRACTION	2.3
3UIH	X-RAY DIFFRACTION	2.4
1XB1	X-RAY DIFFRACTION	2.7
3UIJ	X-RAY DIFFRACTION	2.71
6JX6	X-RAY DIFFRACTION	2.81
8ATO	ELECTRON MICROSCOPY	3
8E2I	ELECTRON MICROSCOPY	3.04
8E2J	ELECTRON MICROSCOPY	3.44
8AUW	ELECTRON MICROSCOPY	7.2
1G3F	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR28-F1	82.53	0.61

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 55–56 (cleavage; by parl)

Mutagenesis-validated functional residues (2):

Position	Phenotype
81	monomeric. impairs interaction with birc6. impairs ability to inhibit birc6 caspase ubiquitination.
56	fails to inhibit birc6 activity. fails to inhibit digestion of birc6 by casp3, casp7 or htra2 mutant ‘a-306’.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-111457	Release of apoptotic factors from the mitochondria
R-HSA-111463	SMAC (DIABLO) binds to IAPs
R-HSA-111464	SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes
R-HSA-111469	SMAC, XIAP-regulated apoptotic response
R-HSA-9627069	Regulation of the apoptosome activity

MSigDB gene sets: 154 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, CREBP1_Q2, USF_C, GOBP_APOPTOTIC_SIGNALING_PATHWAY, WANG_LMO4_TARGETS_DN, MYCMAX_01, BRN2_01, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_VIA_DEATH_DOMAIN_RECEPTORS, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_NEURON_APOPTOTIC_PROCESS, LAU_APOPTOSIS_CDKN2A_UP

GO Biological Process (7): apoptotic process (GO:0006915), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), intrinsic apoptotic signaling pathway in response to oxidative stress (GO:0008631), positive regulation of apoptotic process (GO:0043065), neuron apoptotic process (GO:0051402), apoptotic signaling pathway (GO:0097190), intrinsic apoptotic signaling pathway (GO:0097193)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (11): mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758), centriole (GO:0005814), cytosol (GO:0005829), cytoplasmic side of plasma membrane (GO:0009898), CD40 receptor complex (GO:0035631), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Apoptotic factor-mediated response	2
SMAC, XIAP-regulated apoptotic response	2
Formation of apoptosome	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
apoptotic process	3
sperm flagellum	3
apoptotic signaling pathway	2
cytoplasm	2
programmed cell death	1
execution phase of apoptosis	1
extrinsic apoptotic signaling pathway	1
intrinsic apoptotic signaling pathway	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
signal transduction	1
intracellular signal transduction	1
binding	1
intracellular membrane-bounded organelle	1
mitochondrial envelope	1
organelle envelope lumen	1
microtubule organizing center	1
intracellular membraneless organelle	1
plasma membrane	1
cytoplasmic side of membrane	1
plasma membrane signaling receptor complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIABLO	XIAP	P98170	999
DIABLO	BIRC2	Q13490	997
DIABLO	APAF1	O14727	986
DIABLO	CYCS	P00001	982
DIABLO	CASP9	P55211	964
DIABLO	BIRC3	Q13489	938
DIABLO	HTRA2	O43464	934
DIABLO	KCNJ11	Q14654	924
DIABLO	ENDOG	Q14249	908
DIABLO	BCL2	P10415	884
DIABLO	BIRC7	Q96CA5	883
DIABLO	CASP8	Q14790	874
DIABLO	CASP3	P42574	864
DIABLO	CUL3	Q13618	802
DIABLO	CASP7	P55210	779

IntAct

195 interactions, top by confidence:

A	B	Type	Score
XIAP	HTRA2	psi-mi:“MI:0914”(association)	0.960
BIRC2	TRAF2	psi-mi:“MI:0914”(association)	0.950
DIABLO	XIAP	psi-mi:“MI:0915”(physical association)	0.940
XIAP	DIABLO	psi-mi:“MI:0915”(physical association)	0.940
DIABLO	XIAP	psi-mi:“MI:0407”(direct interaction)	0.940
BIRC2	DIABLO	psi-mi:“MI:0915”(physical association)	0.870
BIRC2	DIABLO	psi-mi:“MI:0407”(direct interaction)	0.870
DIABLO	BIRC2	psi-mi:“MI:0407”(direct interaction)	0.870
DIABLO	BIRC2	psi-mi:“MI:0915”(physical association)	0.870
BIRC3	TRAF2	psi-mi:“MI:0914”(association)	0.860
ARL6IP1	DIABLO	psi-mi:“MI:0915”(physical association)	0.810
DIABLO	ARL6IP1	psi-mi:“MI:0915”(physical association)	0.810
TRAF2	HTRA2	psi-mi:“MI:0914”(association)	0.750
MTFR1	DIABLO	psi-mi:“MI:0915”(physical association)	0.740
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
DIABLO	AGTRAP	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (462): DIABLO (Affinity Capture-Western), DIABLO (Affinity Capture-Western), DIABLO (Biochemical Activity), DIABLO (Two-hybrid), DIABLO (Affinity Capture-Western), DIABLO (Reconstituted Complex), DIABLO (Reconstituted Complex), DIABLO (Biochemical Activity), DIABLO (Biochemical Activity), DIABLO (Affinity Capture-Western), DIABLO (Affinity Capture-MS), DIABLO (Affinity Capture-MS), DIABLO (Affinity Capture-MS), DIABLO (Affinity Capture-Western), PRKCD (Affinity Capture-Western)

ESM2 similar proteins: A3KQI3, A4GZV0, B4URD8, P03485, P05775, P08381, P33885, P35259, P36347, Q01048, Q08IG8, Q0A2D5, Q0A2H4, Q0A435, Q0A446, Q0A457, Q0IJ31, Q20NV9, Q20P02, Q20PM1, Q2Y2M6, Q4S3C1, Q5RBH2, Q64904, Q64912, Q64919, Q67147, Q67169, Q67173, Q67177, Q67187, Q67202, Q67204, Q6WBA1, Q6XTU9, Q76V02, Q76V03, Q76V05, Q77W48, Q77ZK7

Diamond homologs: A4GZV0, Q0IJ31, Q5RBH2, Q9JIQ3, Q9NR28

SIGNOR signaling

29 interactions.

A	Effect	B	Mechanism
HSPB1	down-regulates	DIABLO
DIABLO	“down-regulates activity”	XIAP	binding
DIABLO	“down-regulates quantity”	XIAP	binding
BAK1	up-regulates	DIABLO	relocalization
DIABLO	“down-regulates quantity”	BIRC2	binding
DIABLO	“down-regulates quantity”	BIRC3	binding
BIRC7	down-regulates	DIABLO	binding
BIRC5	down-regulates	DIABLO	binding
DIABLO	down-regulates	BIRC5	binding
MAPK10	down-regulates	DIABLO	phosphorylation
BAK1	up-regulates	DIABLO
BAX	up-regulates	DIABLO
DIABLO	down-regulates	XIAP	binding
AREL1	“down-regulates quantity by destabilization”	DIABLO	ubiquitination
BIRC3	“down-regulates quantity by destabilization”	DIABLO	ubiquitination
BIRC2	“down-regulates quantity by destabilization”	DIABLO	ubiquitination
MAPK8	“up-regulates activity”	DIABLO	phosphorylation
DIABLO	“down-regulates activity”	BIRC3	binding
DIABLO	up-regulates	CASP9
DIABLO	“down-regulates activity”	BIRC2	binding
BAX	up-regulates	DIABLO	relocalization
BCL2	down-regulates	DIABLO
XIAP	“down-regulates quantity by destabilization”	DIABLO	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 124 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TNFR1-induced NF-kappa-B signaling pathway	9	35.1×	1e-09
TICAM1, RIP1-mediated IKK complex recruitment	5	34.9×	2e-05
TNFR1-induced proapoptotic signaling	6	30.6×	5e-06
IKK complex recruitment mediated by RIP1	5	28.9×	5e-05
NOD1/2 Signaling Pathway	7	25.8×	2e-06
Regulation of necroptotic cell death	5	25.5×	8e-05
Regulation of TNFR1 signaling	9	23.4×	4e-08
TNFR2 non-canonical NF-kB pathway	7	14.8×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
canonical NF-kappaB signal transduction	7	24.2×	1e-05
tumor necrosis factor-mediated signaling pathway	7	21.8×	1e-05
positive regulation of protein ubiquitination	8	16.1×	1e-05
protein K63-linked ubiquitination	5	12.6×	4e-03
aerobic respiration	5	11.7×	5e-03
positive regulation of JNK cascade	7	10.8×	7e-04
obsolete positive regulation of NF-kappaB transcription factor activity	5	9.7×	8e-03
positive regulation of canonical NF-kappaB signal transduction	9	6.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

128 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	59
Likely benign	35
Benign	15

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3250382	NM_001371333.1(DIABLO):c.248_251del (p.Asp83fs)	Likely pathogenic
3601069	NM_001371333.1(DIABLO):c.381GGA[1] (p.Glu129del)	Likely pathogenic

SpliceAI

1303 predictions. Top by Δscore:

Variant	Effect	Δscore
12:122209771:A:AC	donor_gain	1.0000
12:122209772:C:CC	donor_gain	1.0000
12:122209772:CTG:C	donor_gain	1.0000
12:122216479:TGA:T	donor_gain	1.0000
12:122216483:CCTA:C	donor_loss	1.0000
12:122216484:CTA:C	donor_loss	1.0000
12:122216485:TA:T	donor_loss	1.0000
12:122216485:TAC:T	donor_loss	1.0000
12:122216486:A:AC	donor_gain	1.0000
12:122216486:A:AG	donor_loss	1.0000
12:122216487:C:CC	donor_gain	1.0000
12:122216487:C:CT	donor_loss	1.0000
12:122216487:CCAG:C	donor_gain	1.0000
12:122216487:CCAGT:C	donor_gain	1.0000
12:122216582:CAT:C	acceptor_gain	1.0000
12:122216583:AT:A	acceptor_gain	1.0000
12:122216583:ATCTA:A	acceptor_loss	1.0000
12:122216584:TC:T	acceptor_loss	1.0000
12:122216585:C:CA	acceptor_loss	1.0000
12:122216585:C:CC	acceptor_gain	1.0000
12:122216587:A:C	acceptor_gain	1.0000
12:122216866:CAGC:C	acceptor_gain	1.0000
12:122216868:GCC:G	acceptor_loss	1.0000
12:122216869:CCTA:C	acceptor_loss	1.0000
12:122216870:C:CG	acceptor_loss	1.0000
12:122216871:T:C	acceptor_loss	1.0000
12:122216482:ACCT:A	donor_loss	0.9900
12:122216486:AC:A	donor_gain	0.9900
12:122216487:CC:C	donor_gain	0.9900
12:122216487:CCA:C	donor_gain	0.9900

AlphaMissense

1537 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:122216503:C:G	A170P	0.997
12:122218286:C:G	A99P	0.996
12:122218329:G:C	S84R	0.996
12:122218329:G:T	S84R	0.996
12:122218331:T:G	S84R	0.996
12:122216499:G:T	A171E	0.995
12:122216512:C:G	A167P	0.995
12:122216532:G:T	A160E	0.995
12:122216533:C:G	A160P	0.995
12:122216542:A:G	W157R	0.995
12:122216542:A:T	W157R	0.995
12:122218315:A:G	L89P	0.995
12:122216509:C:G	A168P	0.994
12:122216500:C:G	A171P	0.993
12:122216770:C:G	A139P	0.993
12:122216869:C:G	A106P	0.992
12:122216523:A:G	L163P	0.990
12:122218352:C:G	A77P	0.990
12:122208491:C:G	A204P	0.989
12:122208575:C:G	A176P	0.989
12:122216847:A:G	L113P	0.988
12:122218315:A:T	L89H	0.988
12:122216511:G:T	A167E	0.987
12:122216521:A:G	S164P	0.987
12:122218303:G:T	T93K	0.987
12:122218318:A:G	F88S	0.987
12:122216540:C:A	W157C	0.986
12:122216540:C:G	W157C	0.986
12:122216765:T:A	R140S	0.986
12:122216765:T:G	R140S	0.986

dbSNP variants (sampled 300 via entrez): RS1000080971 (12:122213520 A>T), RS1000288041 (12:122229176 C>T), RS1000399869 (12:122228549 C>A), RS1000600859 (12:122227514 C>A,T), RS1000631942 (12:122227740 G>A,C), RS1000644514 (12:122223782 G>T), RS1000861715 (12:122225469 T>C), RS1000923317 (12:122218769 G>A), RS1001526686 (12:122223163 G>A), RS1001527942 (12:122222816 G>A), RS1001587843 (12:122215831 T>G), RS1001653934 (12:122227996 A>G,T), RS1001721889 (12:122209985 T>G), RS1001918178 (12:122217311 G>A), RS1001918743 (12:122224506 C>T)

Disease associations

OMIM: gene MIM:605219 | disease phenotypes: MIM:614152, MIM:124900

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
nonsyndromic genetic hearing loss	Limited	Autosomal dominant
autosomal dominant nonsyndromic hearing loss 64	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AD

Mondo (3): autosomal dominant nonsyndromic hearing loss 64 (MONDO:0013593), autosomal dominant nonsyndromic hearing loss (MONDO:0019587), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (1): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000360	Tinnitus
HP:0000407	Sensorineural hearing impairment
HP:0003621	Juvenile onset
HP:0003676	Progressive
HP:0011462	Young adult onset

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST90020024_239	A body shape index	7.000000e-09
GCST90020025_114	Waist-to-hip ratio adjusted for BMI	3.000000e-13
GCST90020027_1192	Waist-hip index	6.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

135 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Bortezomib	affects localization, increases expression, increases secretion, decreases localization, decreases reaction (+3 more)	8
bisphenol A	affects expression, increases abundance, decreases expression, increases expression, affects cotreatment	4
alvocidib	increases secretion, affects localization, affects cotreatment	4
trichostatin A	affects cotreatment, decreases expression	3
Cannabidiol	decreases reaction, increases reaction, affects cotreatment, affects localization, decreases expression (+4 more)	3
Doxorubicin	affects cotreatment, increases expression, increases reaction, affects expression, increases response to substance	3
Quercetin	affects localization, increases expression, increases localization	3
Tretinoin	increases expression, decreases expression, affects cotreatment, affects localization	3
Paclitaxel	affects cotreatment, affects localization, increases expression	3
Thapsigargin	increases expression, affects response to substance, affects localization	3
Particulate Matter	decreases expression, decreases reaction, increases abundance, increases expression	3
fludarabine	affects cotreatment, increases secretion, affects localization	2
ochratoxin A	decreases expression	2
phenethyl isothiocyanate	affects binding, affects localization, decreases reaction	2
pterostilbene	affects localization, increases expression	2
corosolic acid	decreases expression	2
LAQ824	affects cotreatment, affects localization	2
Sorafenib	affects cotreatment, affects localization, increases reaction, decreases reaction	2
Resveratrol	affects localization, affects cotreatment	2
Vehicle Emissions	decreases expression, decreases reaction, increases abundance, increases expression	2
Cisplatin	increases response to substance	2
Curcumin	affects cotreatment, increases expression	2
Dexamethasone	affects localization, affects cotreatment	2
Fluorouracil	increases expression, increases response to substance	2
Melatonin	increases expression, increases reaction, decreases reaction, affects cotreatment	2
Paraquat	decreases reaction, increases transport, affects localization	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Vitamin E	affects localization, decreases reaction	2
aristolochic acid I	increases expression	1
UMI-77	affects localization	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_HD75	HCT 116 DIABLO(-/-)	Cancer cell line	Male
CVCL_KT51	HeLa SilenciX DIABLO	Cancer cell line	Female

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations