VPS4B

Summary

VPS4B (vacuolar protein sorting 4 homolog B, HGNC:10895) is a protein-coding gene on chromosome 18q21.33, encoding Vacuolar protein sorting-associated protein 4B (O75351). Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. It is a selective cancer dependency (DepMap: 12.4% of cell lines).

The protein encoded by this gene is a member of the AAA protein family (ATPases associated with diverse cellular activities), and is the homolog of the yeast Vps4 protein. In humans, two paralogs of the yeast protein have been identified. The former share a high degree of aa sequence similarity with each other, and also with yeast Vps4 and mouse Skd1 proteins. Mouse Skd1 (suppressor of K+ transport defect 1) has been shown to be a yeast Vps4 ortholog. Functional studies indicate that both human paralogs associate with the endosomal compartments, and are involved in intracellular protein trafficking, similar to Vps4 protein in yeast. The gene encoding this paralog has been mapped to chromosome 18; the gene for the other resides on chromosome 16.

Source: NCBI Gene 9525 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dentin dysplasia type I (Supportive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 51 total — 2 pathogenic
• Phenotypes (HPO): 6
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 12.4% of screened cell lines
• MANE Select transcript: NM_004869

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10895
Approved symbol	VPS4B
Name	vacuolar protein sorting 4 homolog B
Location	18q21.33
Locus type	gene with protein product
Status	Approved
Aliases	VPS4-2, SKD1B
Ensembl gene	ENSG00000119541
Ensembl biotype	protein_coding
OMIM	609983
Entrez	9525

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000238497, ENST00000588059, ENST00000588323, ENST00000589604, ENST00000591383, ENST00000591475, ENST00000591519, ENST00000863557, ENST00000930477, ENST00000930478, ENST00000930479, ENST00000930480

RefSeq mRNA: 1 — MANE Select: NM_004869 NM_004869

CCDS: CCDS11983

Canonical transcript exons

ENST00000238497 — 11 exons

Exon	Start	End
ENSE00000670223	63393409	63393549
ENSE00001104872	63389190	63391076
ENSE00003494713	63411467	63411578
ENSE00003502406	63410290	63410446
ENSE00003567153	63399242	63399323
ENSE00003580437	63400547	63400703
ENSE00003581079	63400048	63400196
ENSE00003597671	63397034	63397253
ENSE00003602912	63407432	63407499
ENSE00003634832	63403707	63403826
ENSE00003847975	63422233	63422476

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.9263 / max 196.6913, expressed in 1797 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172284	14.1860	1776
172283	4.9344	1573
172282	0.6394	349
172281	0.1664	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	99.46	gold quality
epithelium of esophagus	UBERON:0001976	98.78	gold quality
endothelial cell	CL:0000115	98.73	gold quality
amniotic fluid	UBERON:0000173	98.52	gold quality
squamous epithelium	UBERON:0006914	98.47	gold quality
tongue squamous epithelium	UBERON:0006919	98.37	gold quality
epithelium of nasopharynx	UBERON:0001951	97.87	gold quality
nasopharynx	UBERON:0001728	97.85	gold quality
secondary oocyte	CL:0000655	97.82	gold quality
gingival epithelium	UBERON:0001949	97.52	gold quality
ileal mucosa	UBERON:0000331	97.34	gold quality
gingiva	UBERON:0001828	97.28	gold quality
oral cavity	UBERON:0000167	97.24	gold quality
calcaneal tendon	UBERON:0003701	96.68	gold quality
palpebral conjunctiva	UBERON:0001812	96.61	gold quality
hair follicle	UBERON:0002073	96.25	gold quality
cervix squamous epithelium	UBERON:0006922	96.15	gold quality
pharyngeal mucosa	UBERON:0000355	96.11	gold quality
lower esophagus mucosa	UBERON:0035834	95.96	gold quality
colonic mucosa	UBERON:0000317	95.83	gold quality
pancreatic ductal cell	CL:0002079	95.80	gold quality
germinal epithelium of ovary	UBERON:0001304	95.80	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.77	gold quality
esophagus mucosa	UBERON:0002469	95.68	gold quality
cervix epithelium	UBERON:0004801	95.68	gold quality
skin of hip	UBERON:0001554	95.35	gold quality
upper leg skin	UBERON:0004262	95.29	gold quality
colonic epithelium	UBERON:0000397	95.07	gold quality
tonsil	UBERON:0002372	94.91	gold quality
parietal pleura	UBERON:0002400	94.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.90
E-MTAB-6379	no	913.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI3, ZNF236, ZNF91

miRNA regulators (miRDB)

123 targeting VPS4B, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 28)

• The expression and transport of ALG-2 in association with TSG101 and Vps4B are reported. (PMID:16004603)
• We propose that the MIT domain of Vps4b serves as a putative adaptor domain for the ESCRT-III complex involved in endosomal trafficking. (PMID:16018968)
• The crystal structure of monomeric apo human VPS4B was reported. (PMID:16193069)
• Four proteins (TSG101,Hrs,Aip1/Alix, and Vps4B) of the ESCRT (endosomal sorting complex required for transport) machinery were localized in T cells and macrophages by quantitative electron microscpy. (PMID:17014699)
• Upon coexpression of mutated CHMP3, CHMP4B, or CHMP4C forms, as well as of ATPase-defective Vps4A or Vps4B mutants, HBV assembly and egress were potently blocked. (PMID:17553870)
• Here, we report that dominant negative forms of Vps4A, Vps4B, and AIP1 inhibit HTLV-1 budding. (PMID:17601348)
• studies reveal how the VPS4 ATPases recognize their CHMP substrates to facilitate the membrane fission events required for the release of viruses, endosomal vesicles and daughter cells (PMID:17928862)
• ATP hydrolysis would eliminate this interaction and subsequent nucleotide release causes the domains to rotate, which together lead to the disassembly of the SKD1 oligomer (PMID:18796009)
• Overall, we see no role for the ESCRT pathway in influenza virus budding and the significance of the M1-VPS28 interaction remains to be determined. (PMID:19524996)
• ESCRT-III/VPS4 proteins function at centrosomes to help regulate their maintenance or proliferation and then at midbodies during abscission, thereby helping ensure the ordered progression through the different stages of cell division. (PMID:20616062)
• It was found that neither siRNA knockdown of VPS4A and VPS4B expression nor the use of cell lines that inducibly express VPS4A or VPS4B dominant negative mutants, inhibited influenza virus budding. (PMID:20621136)
• An inverse correlation between VPS4B expression and EGFR abundance is observed in breast tumors, and high-grade or recurrent breast carcinomas exhibit lower VPS4B expression. (PMID:22252323)
• Taken together, it was concluded that VPS4B and its DN mutant VPS4B-K180Q have anti-HBV effect in vivo, which helps develop molecular therapeutic strategies for HBV infection. (PMID:22684550)
• VPS4B may promote the progression of Carcinoma, Non-Small-Cell Lung (NSCLC) and be a biotarget for NSCLCs therapy. (PMID:23737133)
• Protein kinase CK2 alpha is involved in the phosphorylation of the ESCRT-III subunits CHMP3 and CHMP2B, as well as of VPS4B/SKD1, an ATPase that mediates ESCRT-III disassembly. (PMID:24440309)
• High Vacuolar protein sorting 4B results in more apoptosis of intestinal epithelial cells via p38 MAPK in Crohn’s disease. (PMID:25533544)
• Lack of ALG-2, ALIX or Vps4B each prevents shedding, and repair of the injured cell membrane (PMID:25534348)
• ESCRT-III protein CHMP5 inhibits LIP5-mediated VPS4 activation by inducing a moderate conformational change within LIP5. (PMID:25637630)
• Crystal structures of three molecular complexes reveal that IST1 binds to the MIT domains of VPS4 and LIP5. (PMID:25657007)
• Our findings support a role for VPS4B in MM cell proliferation, adhesion, and drug resistance, and pave the way for a novel therapeutic approach targeting this molecule. (PMID:25804841)
• Knockdown of vps4b in zebrafish recapitulated the reduction of tooth size. (PMID:27247351)
• VPS4B might facilitate chondrocyte apoptosis in Osteoarthritis via p38 MAPK signaling pathway. (PMID:28744712)
• VPS4B, via Wnt-beta-catenin signalling, acts as a regulator of the proliferation and differentiation of hDPSCs (PMID:31218890)
• Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer. (PMID:31930723)
• VPS4B mutation impairs the osteogenic differentiation of dental follicle cells derived from a patient with dentin dysplasia type I. (PMID:32737282)
• Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q. (PMID:33326793)
• Analysis of individual HIV-1 budding event using fast AFM reveals a multiplexed role for VPS4. (PMID:36042696)
• p-AKT/VPS4B regulates the small extracellular vesicle size in venous malformation endothelial cells. (PMID:37154262)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	vps4b	ENSDARG00000069175
danio_rerio	si:dkey-185p13.1	ENSDARG00000095837
mus_musculus	Vps4b	ENSMUSG00000009907
rattus_norvegicus	Vps4b	ENSRNOG00000002705
drosophila_melanogaster	Vps4	FBGN0283469
caenorhabditis_elegans	vps-4	WBGENE00021334

Paralogs (9): SPAST (ENSG00000021574), KATNAL1 (ENSG00000102781), FIGNL1 (ENSG00000132436), VPS4A (ENSG00000132612), ATAD1 (ENSG00000138138), KATNAL2 (ENSG00000167216), FIGN (ENSG00000182263), KATNA1 (ENSG00000186625), FIGNL2 (ENSG00000261308)

Protein

Protein identifiers

Vacuolar protein sorting-associated protein 4B — O75351 (reviewed: O75351)

Alternative names: Cell migration-inducing gene 1 protein, Suppressor of K(+) transport growth defect 1

All UniProt accessions (3): O75351, K7EKZ3, K7EL71

UniProt curated annotations — full annotation on UniProt →

Function. Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly, possibly in combination with membrane fission. Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan. (Microbial infection) In conjunction with the ESCRT machinery also appears to function in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and enveloped virus budding (HIV-1 and other lentiviruses).

Subunit / interactions. Proposed to be monomeric or homodimeric in nucleotide-free form and to oligomerize upon binding to ATP to form two stacked hexameric or heptameric rings with a central pore through which ESCRT-III substrates are translocated in an ATP-dependent manner. In vitro, associates on the inside of a helical tubular structure formed by a CHMP2A-CHMP3 polymer. Interacts with CHMP1A, CHMP1B, CHMP2A, CHMP4B and CHMP6. Interacts with VPS4A; the interaction suggests a heteromeric assembly with VPS4A. Interacts with VTA1.

Subcellular location. Late endosome membrane.

Tissue specificity. Ubiquitously expressed.

Domain organisation. The MIT domain serves as an adapter for ESCRT-III proteins. It forms an asymmetric three-helix bundle that binds amphipathic MIM (MIT interacting motif) helices along the groove between MIT helices 2 and 3 present in a subset of ESCRT-III proteins thus establishing the canonical MIM-MIT interaction. In an extended conformation along the groove between helices 1 and 3, also binds to a type-2 MIT interacting motif (MIM2).

Similarity. Belongs to the AAA ATPase family.

RefSeq proteins (1): NP_004860* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR007330	MIT_dom	Domain
IPR015415	Spast_Vps4_C	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036181	MIT_dom_sf	Homologous_superfamily
IPR041569	AAA_lid_3	Domain
IPR045253	VPS4_MIT	Domain
IPR050304	MT-severing_AAA_ATPase	Family

Pfam: PF00004, PF04212, PF09336, PF17862

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (58 total): helix 19, strand 13, mutagenesis site 8, turn 4, modified residue 4, sequence conflict 3, chain 1, domain 1, sequence variant 1, region of interest 1, coiled-coil region 1, compositionally biased region 1, binding site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4U7Y	X-RAY DIFFRACTION	2.5
1XWI	X-RAY DIFFRACTION	2.8
7L9X	X-RAY DIFFRACTION	2.81
1WR0	SOLUTION NMR
2CPT	SOLUTION NMR
2JQH	SOLUTION NMR
2JQK	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75351-F1	86.31	0.66

Functional residue map

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

Ligand- & substrate-binding residues (1): 174–181

Post-translational modifications (4): 93, 102, 108, 410

Mutagenesis-validated functional residues (8):

Position	Phenotype
15	reduces hiv-1 release 10-fold; when associated with d-66.
15	reduces hiv-1 release 2-fold.
66	reduces hiv-1 release 10-fold; when associated with d-15.
66	reduces hiv-1 release 3-fold.
208–209	strongly impairs hiv-1 release.
210	impairs hiv-1 release.
235	defective in vacuolar protein sorting.
390–396	abolishes interaction with vta1.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-162588	Budding and maturation of HIV virion
R-HSA-917729	Endosomal Sorting Complex Required For Transport (ESCRT)

MSigDB gene sets: 324 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_MITOTIC_CYTOKINESIS, REACTOME_ENDOSOMAL_SORTING_COMPLEX_REQUIRED_FOR_TRANSPORT_ESCRT, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NUCLEAR_MEMBRANE_REASSEMBLY, GOBP_LYSOSOMAL_TRANSPORT, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOBP_VESICLE_LOCALIZATION, GOBP_MEMBRANE_BIOGENESIS, GOBP_VESICLE_ORGANIZATION, GOBP_CHROMOSOME_LOCALIZATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT

GO Biological Process (41): angiogenesis (GO:0001525), plasma membrane repair (GO:0001778), potassium ion transport (GO:0006813), autophagy (GO:0006914), nucleus organization (GO:0006997), vacuole organization (GO:0007033), mitotic metaphase chromosome alignment (GO:0007080), regulation of centrosome duplication (GO:0010824), positive regulation of G2/M transition of mitotic cell cycle (GO:0010971), protein transport (GO:0015031), endosomal transport (GO:0016197), macroautophagy (GO:0016236), cholesterol transport (GO:0030301), nuclear membrane reassembly (GO:0031468), endosome to lysosome transport via multivesicular body sorting pathway (GO:0032510), response to lipid (GO:0033993), multivesicular body assembly (GO:0036258), viral budding via host ESCRT complex (GO:0039702), ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043162), viral budding from plasma membrane (GO:0046761), protein depolymerization (GO:0051261), canonical Wnt signaling pathway (GO:0060070), establishment of blood-brain barrier (GO:0060856), late endosomal microautophagy (GO:0061738), late endosome to lysosome transport via multivesicular body sorting pathway (GO:0061764), midbody abscission (GO:0061952), multivesicular body sorting pathway (GO:0071985), membrane fission (GO:0090148), obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway (GO:0090611), autophagosome maturation (GO:0097352), regulation of mitotic spindle assembly (GO:1901673), negative regulation of exosomal secretion (GO:1903542), positive regulation of exosomal secretion (GO:1903543), positive regulation of centriole elongation (GO:1903724), ESCRT III complex disassembly (GO:1904903), endosome organization (GO:0007032), vacuolar transport (GO:0007034), lysosomal transport (GO:0007041), central nervous system development (GO:0007417), regulation of G2/M transition of mitotic cell cycle (GO:0010389)

GO Molecular Function (8): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (15): spindle pole (GO:0000922), nucleus (GO:0005634), nuclear pore (GO:0005643), cytoplasm (GO:0005737), endosome (GO:0005768), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), midbody (GO:0030496), late endosome membrane (GO:0031902), extracellular exosome (GO:0070062), Flemming body (GO:0090543), ATPase complex (GO:1904949), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Late Phase of HIV Life Cycle	1
Membrane Trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
organelle organization	2
viral budding	2
binding	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
plasma membrane organization	1
wound healing	1
metal ion transport	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
mitotic sister chromatid segregation	1
mitotic cell cycle	1
metaphase chromosome alignment	1
mitotic cell cycle process	1
regulation of centrosome cycle	1
centrosome duplication	1
G2/M transition of mitotic cell cycle	1
regulation of G2/M transition of mitotic cell cycle	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of cell cycle G2/M phase transition	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
vesicle-mediated transport	1
intracellular transport	1
autophagosome assembly	1
autophagy	1
sterol transport	1
membrane assembly	1
nuclear membrane organization	1
endosome to lysosome transport	1
endosome transport via multivesicular body sorting pathway	1
response to chemical	1
multivesicular body organization	1
organelle assembly	1
ubiquitin-dependent protein catabolic process	1
protein catabolic process in the vacuole	1
multivesicular body sorting pathway	1

Protein interactions and networks

STRING

1551 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VPS4B	VTA1	Q9NP79	994
VPS4B	CHMP2A	O43633	980
VPS4B	CHMP5	Q9NZZ3	968
VPS4B	CHMP1A	Q9HD42	968
VPS4B	CHMP6	Q96FZ7	956
VPS4B	CHMP4A	Q9BY43	941
VPS4B	A0A140T963	A0A140T963	940
VPS4B	CHMP3	Q9Y3E7	940
VPS4B	PDCD6IP	Q8WUM4	922
VPS4B	CHMP2B	Q9UQN3	921
VPS4B	CHMP4C	Q96CF2	908
VPS4B	TSG101	Q99816	904
VPS4B	CHMP1B	Q7LBR1	881
VPS4B	PDCD6	O75340	851
VPS4B	VPS25	Q9BRG1	819

IntAct

66 interactions, top by confidence:

A	B	Type	Score
ZFYVE19	VPS4B	psi-mi:“MI:0915”(physical association)	0.780
VPS4B	ZFYVE19	psi-mi:“MI:0915”(physical association)	0.780
CHMP5	VPS4B	psi-mi:“MI:0915”(physical association)	0.720
VPS4B	CHMP5	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ZFYVE19	VPS4B	psi-mi:“MI:0915”(physical association)	0.560
VPS4B	ZFYVE19	psi-mi:“MI:0915”(physical association)	0.560
VPS4B	CHMP2B	psi-mi:“MI:0407”(direct interaction)	0.560
VPS4B	KATNAL1	psi-mi:“MI:0915”(physical association)	0.560
VPS4B	CHMP1A	psi-mi:“MI:0915”(physical association)	0.560
VPS4B	HTT	psi-mi:“MI:0915”(physical association)	0.560
VPS4B	ATXN1	psi-mi:“MI:0915”(physical association)	0.560
VPS4B	CFTR	psi-mi:“MI:0915”(physical association)	0.550
VPS4B	BIRC2	psi-mi:“MI:0914”(association)	0.530
VPS4A	VPS4B	psi-mi:“MI:0914”(association)	0.530
	AP3D1	psi-mi:“MI:0914”(association)	0.460
	MYL12B	psi-mi:“MI:0914”(association)	0.460

BioGRID (126): CHMP5 (Two-hybrid), ZFYVE19 (Two-hybrid), VPS4B (Affinity Capture-RNA), VPS4B (Affinity Capture-MS), VPS4B (Affinity Capture-MS), BIRC2 (Affinity Capture-MS), ITPA (Affinity Capture-MS), VTA1 (Affinity Capture-MS), RBM14-RBM4 (Affinity Capture-MS), PRKCA (Affinity Capture-MS), VPS13A (Co-fractionation), VPS45 (Co-fractionation), VPS4B (Co-fractionation), VPS4B (Co-fractionation), VPS4B (Co-fractionation)

ESM2 similar proteins: B4F6J6, D0FH76, F6QV99, O75351, P03974, P18708, P23787, P28737, P46459, P46460, P46461, P46462, P46467, P52917, P54351, P54609, P54774, P54811, P54812, P54815, P55072, Q01853, Q09803, Q0DGP6, Q0VD48, Q3ZBT1, Q503W7, Q505J9, Q54PT2, Q5AG40, Q5R410, Q5R658, Q6GL04, Q75JI3, Q793F9, Q7KN62, Q7ZU99, Q7ZZ25, Q8NBU5, Q8VEJ9

Diamond homologs: A0JMA9, A2VDN5, A4IHT0, A8QFF6, A8XV40, A9RA82, B2RYN7, B3EX35, B3M301, B3P8A3, B4G437, B4HGG6, B4JII0, B4K799, B4M0H8, B4NBP4, B4PL32, B4QSF0, B4USW8, B5X3X5, B7NZ88, B7PXE3, D0FH76, D2VS83, F2Z6D2, F4JEX5, F6QV99, O05209, O16299, O28972, O43078, O61577, O75351, O75449, P25694, P34808, P39955, P40328, P46467, P52917

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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.

GO biological processes:

GO term	Partners	Fold	FDR
nuclear membrane reassembly	5	107.8×	4e-08
viral budding via host ESCRT complex	6	104.7×	5e-09
midbody abscission	6	95.6×	5e-09
multivesicular body sorting pathway	5	87.2×	1e-07
nucleus organization	6	73.3×	1e-08
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	6	70.9×	2e-08
multivesicular body assembly	6	68.7×	2e-08
plasma membrane repair	5	63.2×	5e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	39
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1526623	GRCh37/hg19 18q21.2-23(chr18:52837852-77989426)	Pathogenic
4538522	VPS4B, IVS7, C-G, +46	Pathogenic

SpliceAI

1777 predictions. Top by Δscore:

Variant	Effect	Δscore
18:63391072:TCCGA:T	acceptor_gain	1.0000
18:63391073:CCGA:C	acceptor_gain	1.0000
18:63391073:CCGAC:C	acceptor_gain	1.0000
18:63391074:CGA:C	acceptor_gain	1.0000
18:63391074:CGAC:C	acceptor_gain	1.0000
18:63391077:C:CC	acceptor_gain	1.0000
18:63391081:C:CT	acceptor_gain	1.0000
18:63393437:T:C	donor_gain	1.0000
18:63397224:G:T	acceptor_gain	1.0000
18:63400192:CCAGT:C	acceptor_gain	1.0000
18:63400193:CAGT:C	acceptor_gain	1.0000
18:63400193:CAGTC:C	acceptor_gain	1.0000
18:63400197:C:CC	acceptor_gain	1.0000
18:63400542:CT:C	donor_loss	1.0000
18:63400543:TT:T	donor_loss	1.0000
18:63400544:TACT:T	donor_loss	1.0000
18:63400545:A:AC	donor_gain	1.0000
18:63400545:AC:A	donor_loss	1.0000
18:63400546:C:CA	donor_gain	1.0000
18:63400546:CT:C	donor_gain	1.0000
18:63400546:CTT:C	donor_gain	1.0000
18:63400546:CTTTT:C	donor_gain	1.0000
18:63400555:TTC:T	donor_gain	1.0000
18:63400699:CTTGC:C	acceptor_gain	1.0000
18:63400700:TTGC:T	acceptor_gain	1.0000
18:63400702:GCCT:G	acceptor_loss	1.0000
18:63400703:CCTA:C	acceptor_loss	1.0000
18:63400704:C:CC	acceptor_gain	1.0000
18:63400704:CTAA:C	acceptor_loss	1.0000
18:63400705:T:A	acceptor_loss	1.0000

AlphaMissense

2908 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:63391002:A:C	F436L	1.000
18:63391002:A:T	F436L	1.000
18:63391004:A:G	F436L	1.000
18:63397113:C:T	G338E	1.000
18:63397253:T:A	R291S	1.000
18:63397253:T:G	R291S	1.000
18:63399242:C:G	R291T	1.000
18:63399245:C:G	R290P	1.000
18:63399254:G:T	A287D	1.000
18:63399260:T:A	D285V	1.000
18:63399261:C:G	D285H	1.000
18:63399270:A:G	W282R	1.000
18:63399270:A:T	W282R	1.000
18:63399272:G:T	P281H	1.000
18:63399277:A:C	N279K	1.000
18:63399277:A:T	N279K	1.000
18:63399279:T:A	N279Y	1.000
18:63399281:G:A	T278I	1.000
18:63399284:G:T	A277D	1.000
18:63399287:C:T	G276E	1.000
18:63399288:C:G	G276R	1.000
18:63399288:C:T	G276R	1.000
18:63399290:A:G	L275P	1.000
18:63399293:A:T	V274D	1.000
18:63400062:A:G	L259P	1.000
18:63400069:C:T	E257K	1.000
18:63400073:C:A	K255N	1.000
18:63400073:C:G	K255N	1.000
18:63400083:C:G	R252P	1.000
18:63400094:A:C	S248R	1.000

dbSNP variants (sampled 300 via entrez): RS1000047165 (18:63399944 G>C), RS1000086811 (18:63396598 C>T), RS1000117640 (18:63412866 G>A,C), RS1000182322 (18:63395211 C>T), RS1000214865 (18:63395720 C>T), RS1000218891 (18:63414843 C>T), RS1000283985 (18:63403084 C>T), RS1000305838 (18:63390027 A>G), RS1000489691 (18:63409181 G>A), RS1000513120 (18:63393764 G>A), RS1000651317 (18:63401599 C>T), RS1000696544 (18:63388755 C>A,T), RS1000722945 (18:63413978 C>A,T), RS1000794612 (18:63419251 C>T), RS1000809675 (18:63423252 A>G)

Disease associations

OMIM: gene MIM:609983 | disease phenotypes: MIM:621440

GenCC curated gene-disease

Disease	Classification	Inheritance
dentin dysplasia type I	Supportive	Autosomal dominant

Mondo (2): dentin dysplasia, type IB (MONDO:0700387), dentin dysplasia type I (MONDO:0007436)

Orphanet (0):

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0003621	Juvenile onset
HP:0006350	Pulp obliteration
HP:0006480	Premature loss of teeth
HP:0006486	Abnormal dental root morphology
HP:0033784	Dentin dysplasia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002379_6	Pyoderma gangrenosum in inflammatory bowel disease	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006835	pyoderma gangrenosum

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538215	Dentin dysplasia, type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2311229 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.15	IC50	710	nM	CHEMBL4572843

PubChem BioAssay actives

3 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4,4-bis(4-fluorophenyl)-N-[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl]butan-1-amine	1558375: Inhibition of VPS4B (unknown origin) assessed as reduction in ATPase activity in presence of activating fragment of substrate CHMP1B	ic50	0.7100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects cotreatment	3
Tobacco Smoke Pollution	affects expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
coumarin	decreases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	increases expression	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Rotenone	increases expression	1
Urethane	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2317268	Binding	Inhibition of VPS4B (unknown origin) at 10 uM	Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8Y5	Ubigene HCT 116 VPS4B KO	Cancer cell line	Male
CVCL_E1NL	HAP1 VPS4B (-) 2	Cancer cell line	Male
CVCL_E2NW	HAP1 VPS4B (-) 3	Cancer cell line	Male
CVCL_XV03	HAP1 VPS4B (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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