DNAJB8

Summary

DNAJB8 (DnaJ heat shock protein family (Hsp40) member B8, HGNC:23699) is a protein-coding gene on chromosome 3q21.3, encoding DnaJ homolog subfamily B member 8 (Q8NHS0). Efficient suppressor of aggregation and toxicity of disease-associated polyglutamine proteins.

The protein encoded by this gene belongs to the DNAJ/HSP40 family of proteins that regulate chaperone activity. This family member suppresses aggregation and toxicity of polyglutamine proteins, and the C-terminal tail is essential for this activity. It has been implicated as a cancer-testis antigen and as a cancer stem-like cell antigen involved in renal cell carcinoma.

Source: NCBI Gene 165721 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 55 total — 4 pathogenic
• MANE Select transcript: NM_153330

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23699
Approved symbol	DNAJB8
Name	DnaJ heat shock protein family (Hsp40) member B8
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC33884, CT156
Ensembl gene	ENSG00000179407
Ensembl biotype	protein_coding
OMIM	611337
Entrez	165721

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000319153, ENST00000469083

RefSeq mRNA: 1 — MANE Select: NM_153330 NM_153330

CCDS: CCDS3048

Canonical transcript exons

ENST00000319153 — 3 exons

Exon	Start	End
ENSE00001332267	128465276	128465436
ENSE00001332270	128466614	128466890
ENSE00001818226	128462437	128464110

Expression profiles

Bgee: expression breadth broad, 19 present calls, max score 95.72.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1351 / max 114.5756, expressed in 5 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44424	0.1264	5
44425	0.0087	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	95.72	gold quality
left testis	UBERON:0004533	91.05	gold quality
right testis	UBERON:0004534	90.43	gold quality
testis	UBERON:0000473	88.03	gold quality
adult organism	UBERON:0007023	77.84	gold quality
pancreatic ductal cell	CL:0002079	73.65	silver quality
buccal mucosa cell	CL:0002336	66.42	gold quality
tibialis anterior	UBERON:0001385	62.41	silver quality
ileal mucosa	UBERON:0000331	60.14	gold quality
tendon of biceps brachii	UBERON:0008188	59.44	gold quality
myocardium	UBERON:0002349	58.34	gold quality
epithelial cell of pancreas	CL:0000083	56.31	gold quality
pericardium	UBERON:0002407	56.31	gold quality
skin of hip	UBERON:0001554	56.20	silver quality
nasal cavity epithelium	UBERON:0005384	55.61	gold quality
parotid gland	UBERON:0001831	55.56	gold quality
vena cava	UBERON:0004087	55.33	gold quality
deltoid	UBERON:0001476	55.15	silver quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
cartilage tissue	UBERON:0002418	53.73	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
bone marrow cell	CL:0002092	52.36	gold quality
quadriceps femoris	UBERON:0001377	51.81	gold quality
decidua	UBERON:0002450	51.55	gold quality
medial globus pallidus	UBERON:0002477	50.75	gold quality
vastus lateralis	UBERON:0001379	50.42	gold quality
globus pallidus	UBERON:0001875	48.40	gold quality
pharyngeal mucosa	UBERON:0000355	47.81	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	32.14
E-ANND-3	no	1.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting DNAJB8, 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-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-3614-5P	99.30	65.25	837
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-3189-5P	97.55	66.71	655

Literature-anchored findings (GeneRIF, showing 10)

• DNAJB6b and DNAJB8 are superior suppressors of aggregation and toxicity of disease-associated polyglutamine proteins. (PMID:20159555)
• Cancer stem-like cell (CSC) maintenance and that it offers a candidate for CSC-targeting immunotherapy in renal cell carcinoma (PMID:22552285)
• The mechanism of DNAJB6 and DNAJB8 is suppression of polyQ protein aggregation by directly binding the polyQ tract. (PMID:23612975)
• Taken together, the results indicate that DNAJB8 is expressed and has role in CRC CSC/CIC and that DNAJB8 is a novel target of CRC CSC/CIC-targeting immunotherapy. (PMID:24450541)
• DNAJB8 is a central and versatile player in the protein aggregation and degradation system.DNAJB8 protein keeps Parkin C289G mutant protein in a soluble, degradation-competent form. (PMID:27713507)
• Results show that DNAJB8 expression is induced by heat shock stress which increases side population cells and cancer stem-like cells. (PMID:29316077)
• Regulatory inter-domain interactions influence Hsp70 recruitment to the DnaJB8 chaperone. (PMID:33574241)
• Integrative genetic, genomic and transcriptomic analysis of heat shock protein and nuclear hormone receptor gene associations with spontaneous preterm birth. (PMID:34429451)
• DNAJB8 in small extracellular vesicles promotes Oxaliplatin resistance through TP53/MDR1 pathway in colon cancer. (PMID:35165262)
• DNAJB8 oligomerization is mediated by an aromatic-rich motif that is dispensable for substrate activity. (PMID:38508190)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnajb6b	ENSDARG00000020953
danio_rerio	dnajb1b	ENSDARG00000041394
danio_rerio	dnajc18	ENSDARG00000056005
danio_rerio	dnajb1a	ENSDARG00000099383
mus_musculus	Dnajb8	ENSMUSG00000048206
rattus_norvegicus	Dnajb8	ENSRNOG00000081815
drosophila_melanogaster	CG2887	FBGN0030207
drosophila_melanogaster	CG5001	FBGN0031322
drosophila_melanogaster	CG3061	FBGN0038195
drosophila_melanogaster	CG30156	FBGN0050156
drosophila_melanogaster	DnaJ-1	FBGN0263106
caenorhabditis_elegans		WBGENE00001019
caenorhabditis_elegans		WBGENE00001031
caenorhabditis_elegans		WBGENE00001044

Paralogs (11): DNAJB11 (ENSG00000090520), DNAJB6 (ENSG00000105993), DNAJB9 (ENSG00000128590), DNAJB1 (ENSG00000132002), DNAJB2 (ENSG00000135924), DNAJB5 (ENSG00000137094), DNAJB12 (ENSG00000148719), DNAJB4 (ENSG00000162616), DNAJB14 (ENSG00000164031), DNAJB7 (ENSG00000172404), DNAJB13 (ENSG00000187726)

Protein

Protein identifiers

DnaJ homolog subfamily B member 8 — Q8NHS0 (reviewed: Q8NHS0)

All UniProt accessions (2): Q8NHS0, A0A140VJI2

UniProt curated annotations — full annotation on UniProt →

Function. Efficient suppressor of aggregation and toxicity of disease-associated polyglutamine proteins.

Subunit / interactions. Interacts with histone deacetylases HDAC4, HDAC6, and SIRT2, HDAC activity is required for antiaggregation.

Domain organisation. The antiaggregation activity resides in the serine-rich region and the C-terminus.

RefSeq proteins (1): NP_699161* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001623	DnaJ_domain	Domain
IPR018253	DnaJ_domain_CS	Conserved_site
IPR036869	J_dom_sf	Homologous_superfamily
IPR043183	DNJB2/6-like	Family

Pfam: PF00226

UniProt features (10 total): helix 4, chain 1, domain 1, sequence variant 1, mutagenesis site 1, turn 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8DTS	X-RAY DIFFRACTION	0.75
2DMX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NHS0-F1	66.35	0.04

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
216	significant loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 61 (showing top): TGACCTY_ERR1_Q2, CHX10_01, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_PROTEIN_MATURATION, OCT1_03, GOBP_REGULATION_OF_INCLUSION_BODY_ASSEMBLY, GOBP_PROTEIN_FOLDING, AFP1_Q6, chr3q21, CDPCR3HD_01, IK3_01, TTTNNANAGCYR_UNKNOWN, TAATTA_CHX10_01, RNCTGNYNRNCTGNY_UNKNOWN

GO Biological Process (3): protein folding (GO:0006457), negative regulation of inclusion body assembly (GO:0090084), obsolete chaperone-mediated protein folding (GO:0061077)

GO Molecular Function (4): Hsp70 protein binding (GO:0030544), protein folding chaperone (GO:0044183), obsolete unfolded protein binding (GO:0051082), protein-folding chaperone binding (GO:0051087)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cellular process	1
protein maturation	1
negative regulation of cellular component organization	1
inclusion body assembly	1
regulation of inclusion body assembly	1
heat shock protein binding	1
protein-folding chaperone binding	1
molecular_function	1
protein folding	1
protein binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2061 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAJB8	ASB4	Q9Y574	475
DNAJB8	DNAJC6	O75061	451
DNAJB8	HSPA4	P34932	448
DNAJB8	DNAJC12	Q9UKB3	430
DNAJB8	CCDC54	Q8NEL0	420
DNAJB8	HSPB7	Q9UBY9	417
DNAJB8	DNAJC2	Q99543	410
DNAJB8	HTT	P42858	399
DNAJB8	BCL7A	Q4VC05	398
DNAJB8	HSPB6	O14558	380
DNAJB8	XAGE2	Q96GT9	379
DNAJB8	HSPB3	Q12988	378
DNAJB8	SPANXC	Q9NY87	370
DNAJB8	SPANXD	Q9BXN6	370
DNAJB8	HSPB1	P04792	369

IntAct

16 interactions, top by confidence:

A	B	Type	Score
ZMYND19	TNFAIP1	psi-mi:“MI:0914”(association)	0.670
THAP2	OGT	psi-mi:“MI:0914”(association)	0.530
DNAJB8	SCGB2A1	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
EPDR1	NAGA	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
LRRK2	DNAJB8	psi-mi:“MI:0915”(physical association)	0.400
AIRIM	DDX39A	psi-mi:“MI:0914”(association)	0.350
IDI2	LMX1B	psi-mi:“MI:0914”(association)	0.350
MAMDC2	CDAN1	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350

BioGRID (99): DNAJB8 (Affinity Capture-Western), DNAJB8 (Affinity Capture-Western), DNAJB8 (Affinity Capture-MS), DNAJB2 (Affinity Capture-MS), SCGB2A1 (Affinity Capture-MS), C9orf40 (Affinity Capture-MS), MLF1 (Affinity Capture-MS), DGCR14 (Affinity Capture-MS), DNAJB8 (Affinity Capture-MS), DNAJB2 (Affinity Capture-MS), C9orf40 (Affinity Capture-MS), MLF1 (Affinity Capture-MS), DNAJB8 (Affinity Capture-MS), DGCR14 (Affinity Capture-MS), SCGB2A1 (Affinity Capture-MS)

ESM2 similar proteins: G3H0N9, O13633, O35723, O54946, O75190, P25294, P25686, P35191, P39102, P48353, P53940, P78004, P87239, P97554, Q09912, Q0IIE8, Q0III6, Q0WTI8, Q10MW6, Q149L6, Q17438, Q28I38, Q4R7Y5, Q54ED3, Q58DR2, Q5F3Z5, Q5FWN8, Q5R6H3, Q5R8H0, Q5R9A4, Q5UP23, Q5XGU5, Q6AYU3, Q6P642, Q7ZXQ8, Q862Z4, Q8GWW8, Q8NHS0, Q8SRK0, Q8TA83

Diamond homologs: A0A0D1E2P6, A0A0P0VG31, A1BHL1, A1V9Q3, A3MA88, A4SFR5, A5EYE5, A5IIT4, A5ITA7, A6LJ63, A6QHC2, A6U251, A7X2Y0, A8EXP6, A8GMF8, A8GV67, A9IGC5, B0B7R0, B0BBX5, B0TYF3, B0VA24, B0VQ00, B1LCI2, B1YKT0, B2I2G6, B3CP03, B3EE31, B3QPW8, B4S9D0, B7GV08, B7I2B2, B7IFE0, B8DQW8, B9E6X0, B9KAB9, C4L424, O35723, O54946, O75190, O84345

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	46
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1183986	Single allele	Pathogenic
1183987	Single allele	Pathogenic
1183992	Single allele	Pathogenic
1375570	NC_000003.11:g.(?127771396)(128205874_?)del	Pathogenic

SpliceAI

237 predictions. Top by Δscore:

Variant	Effect	Δscore
3:128466836:T:TA	donor_gain	0.9600
3:128466888:GCTCA:G	donor_loss	0.9600
3:128466889:CTCAC:C	donor_loss	0.9600
3:128466890:TCA:T	donor_loss	0.9600
3:128466891:CA:C	donor_loss	0.9600
3:128466892:AC:A	donor_loss	0.9600
3:128466893:CCTG:C	donor_loss	0.9600
3:128463254:G:GC	acceptor_gain	0.9100
3:128463249:C:CT	acceptor_gain	0.8500
3:128463254:G:C	acceptor_gain	0.8300
3:128464106:CAATT:C	acceptor_gain	0.8000
3:128464111:C:CC	acceptor_gain	0.7900
3:128465302:G:C	donor_gain	0.7900
3:128464109:TT:T	acceptor_gain	0.7800
3:128466886:CCGCT:C	donor_loss	0.7800
3:128466887:CGCTC:C	donor_loss	0.7800
3:128466892:A:AC	donor_gain	0.7500
3:128466893:C:CC	donor_gain	0.7500
3:128463243:C:CT	acceptor_gain	0.6900
3:128464107:AATTC:A	acceptor_loss	0.6800
3:128464108:ATTCT:A	acceptor_loss	0.6800
3:128464109:TTCTG:T	acceptor_loss	0.6800
3:128464110:TCT:T	acceptor_loss	0.6800
3:128464112:T:A	acceptor_loss	0.6800
3:128465277:TAC:T	donor_gain	0.6800
3:128465278:ACA:A	donor_gain	0.6800
3:128465279:CAC:C	donor_gain	0.6800
3:128464113:G:C	acceptor_loss	0.6600
3:128466079:G:T	donor_gain	0.6200
3:128466894:C:G	donor_loss	0.6100

AlphaMissense

1545 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:128463108:G:C	F46L	0.999
3:128463108:G:T	F46L	0.999
3:128463110:A:G	F46L	0.999
3:128463155:G:C	H31D	0.999
3:128463109:A:G	F46S	0.998
3:128463153:G:C	H31Q	0.998
3:128463153:G:T	H31Q	0.998
3:128463166:G:T	A27D	0.998
3:128463144:C:A	K34N	0.997
3:128463144:C:G	K34N	0.997
3:128463155:G:T	H31N	0.997
3:128463154:T:C	H31R	0.996
3:128463179:A:C	Y23D	0.996
3:128463089:A:C	Y53D	0.995
3:128463109:A:C	F46C	0.995
3:128463175:C:G	R24P	0.995
3:128463079:A:T	L56Q	0.994
3:128463179:A:G	Y23H	0.994
3:128462934:A:C	F104L	0.993
3:128462934:A:T	F104L	0.993
3:128462936:A:G	F104L	0.993
3:128462946:G:C	F100L	0.993
3:128462946:G:T	F100L	0.993
3:128462948:A:G	F100L	0.993
3:128463098:A:G	S50P	0.993
3:128463163:A:G	L28P	0.993
3:128463176:G:T	R24S	0.993
3:128463092:C:G	A52P	0.992
3:128463110:A:C	F46V	0.991
3:128463122:C:G	A42P	0.991

dbSNP variants (sampled 300 via entrez): RS1000133636 (3:128468796 G>T), RS1000551043 (3:128462236 T>C), RS1000555678 (3:128464411 C>T), RS1000588358 (3:128464656 A>G), RS1001476945 (3:128463887 A>G), RS1001895907 (3:128463926 C>T), RS1002447311 (3:128464791 C>T), RS1002840775 (3:128465180 G>A), RS1003100543 (3:128465429 G>T), RS1003473985 (3:128466429 G>A), RS1003804612 (3:128464854 T>C,G), RS1003849385 (3:128466236 G>C,T), RS1003997553 (3:128463905 C>G), RS1004999809 (3:128465107 C>T), RS1006591037 (3:128466156 G>A)

Disease associations

OMIM: gene MIM:611337 | disease phenotypes: MIM:614038, MIM:614172

GenCC curated gene-disease

Mondo (3): deafness-lymphedema-leukemia syndrome (MONDO:0013540), GATA2 deficiency with susceptibility to MDS/AML (MONDO:0042982), monocytopenia with susceptibility to infections (MONDO:0013607)

Orphanet (2): Deafness-lymphedema-leukemia syndrome (Orphanet:3226), GATA2 deficiency spectrum (Orphanet:228423)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002450_4	Plasma omega-6 polyunsaturated fatty acid levels (gamma-linolenic acid)	3.000000e-06
GCST004898_1	Preterm birth (maternal effect)	2.000000e-12
GCST007611_8	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	9.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005680	omega-6 polyunsaturated fatty acid measurement
EFO:0003917	premature birth
EFO:0005939	parental genotype effect measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
terbufos	increases methylation	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Valproic Acid	increases methylation	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04844177	PHASE2	UNKNOWN	Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT01905826	Not specified	RECRUITING	Natural History Study of GATA2 Deficiency and Related Disorders