PDCD6IP

Summary

PDCD6IP (programmed cell death 6 interacting protein, HGNC:8766) is a protein-coding gene on chromosome 3p22.3, encoding Programmed cell death 6-interacting protein (Q8WUM4). Multifunctional protein involved in endocytosis, multivesicular body biogenesis, membrane repair, cytokinesis, apoptosis and maintenance of tight junction integrity. It is a selective cancer dependency (DepMap: 39.3% of cell lines).

This gene encodes a protein that functions within the ESCRT pathway in the abscission stage of cytokinesis, in intralumenal endosomal vesicle formation, and in enveloped virus budding. Studies using mouse cells have shown that overexpression of this protein can block apoptosis. In addition, the product of this gene binds to the product of the PDCD6 gene, a protein required for apoptosis, in a calcium-dependent manner. This gene product also binds to endophilins, proteins that regulate membrane shape during endocytosis. Overexpression of this gene product and endophilins results in cytoplasmic vacuolization, which may be partly responsible for the protection against cell death. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. Related pseudogenes have been identified on chromosome 15.

Source: NCBI Gene 10015 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly 29, primary, autosomal recessive (Strong, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 143 total — 1 pathogenic
• GTEx eGene: eQTL in 34 tissues, sQTL in 6 (q < 0.05)
• Phenotypes (HPO): 35
• Cancer dependency (DepMap): dependent in 39.3% of screened cell lines
• Constraint (gnomAD): pLI 0.19 (intermediate), LOEUF 0.58 (moderately constrained)
• MANE Select transcript: NM_013374

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8766
Approved symbol	PDCD6IP
Name	programmed cell death 6 interacting protein
Location	3p22.3
Locus type	gene with protein product
Status	Approved
Aliases	Alix, AIP1, Hp95
Ensembl gene	ENSG00000170248
Ensembl biotype	protein_coding
OMIM	608074
Entrez	10015

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 17 protein_coding, 11 nonsense_mediated_decay, 6 retained_intron, 5 protein_coding_CDS_not_defined

MANE Select: ENST00000307296

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 3, TSL 3: 6, TSL 4: 4, TSL 5: 2

ENST00000307296, ENST00000412887, ENST00000413073, ENST00000430877, ENST00000435909, ENST00000457054, ENST00000459659, ENST00000465122, ENST00000473593, ENST00000477798, ENST00000482561, ENST00000484478, ENST00000487821, ENST00000489869, ENST00000494810, ENST00000495235, ENST00000498147, ENST00000648706, ENST00000866273, ENST00000866274, ENST00000866275, ENST00000965903, ENST00000965904, ENST00000965905, ENST00000965906, ENST00000965907, ENST00000965908, ENST00001003012, ENST00001049267, ENST00001049270, ENST00001049273, ENST00001049274, ENST00001049275, ENST00001049276, ENST00001096469, ENST00001121735, ENST00001128031, ENST00001129463, ENST00001144549

RefSeq mRNA: 3 — MANE Select: NM_013374 NM_001162429, NM_001256192, NM_013374

CCDS: CCDS2660, CCDS54561

Canonical transcript exons

ENST00000307296 — 18 exons

Exon	Start	End
ENSE00001140976	33841897	33842074
ENSE00001141009	33826480	33826580
ENSE00001218677	33866351	33869703
ENSE00001884181	33798630	33798937
ENSE00003461155	33865243	33865430
ENSE00003491693	33836044	33836266
ENSE00003500313	33825187	33825340
ENSE00003508870	33844112	33844223
ENSE00003536491	33812072	33812126
ENSE00003553429	33845419	33845588
ENSE00003563986	33821955	33822082
ENSE00003565951	33853879	33854013
ENSE00003585606	33838204	33838327
ENSE00003617166	33864006	33864129
ENSE00003634089	33828853	33828969
ENSE00003637613	33852488	33852736
ENSE00003647437	33855166	33855260
ENSE00003650941	33813559	33813628

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 72.1280 / max 471.9426, expressed in 1827 samples.

Highest expression (Bgee): calcaneal tendon, nerve, tibial nerve, stromal cell of endometrium, rectum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PDCD6IP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 34 tissues and its splicing (sQTL) in 6 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 40 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	8.9e-77	-0.35	3:33815563:G:T
Artery Aorta	eqtl	5.8e-55	-0.48	3:33798622:T:C
Artery Tibial	eqtl	4.0e-53	-0.40	3:33818363:T:C
Muscle Skeletal	eqtl	2.6e-49	+0.27	3:33798622:T:C
Brain Cerebellar Hemisphere	eqtl	6.5e-48	+0.66	3:33798622:T:C
Brain Cerebellum	eqtl	6.8e-30	+0.64	3:33799573:A:G
Cells EBV-transformed lymphocytes	eqtl	2.3e-28	-0.44	3:33798622:T:C
Skin Sun Exposed Lower leg	eqtl	1.0e-27	-0.25	3:33840642:G:T
Adipose Subcutaneous	eqtl	3.3e-23	-0.28	3:33798622:T:C
Skin Not Sun Exposed Suprapubic	eqtl	3.7e-22	-0.27	3:33798622:T:C
Esophagus Mucosa	eqtl	3.9e-22	-0.13	3:33856540:T:C
Thyroid	eqtl	9.5e-22	-0.24	3:33824120:G:A
Pituitary	eqtl	2.5e-20	-0.60	3:33824120:G:A
Lung	eqtl	3.0e-18	-0.27	3:33798622:T:C
Pancreas	eqtl	3.1e-17	-0.28	3:33798622:T:C
Stomach	eqtl	5.4e-16	-0.28	3:33836134:G:A
Colon Transverse	eqtl	1.6e-10	-0.15	3:33860457:G:A
Artery Coronary	eqtl	2.8e-10	-0.34	3:33798622:T:C
Adipose Visceral Omentum	eqtl	5.9e-09	-0.20	3:33863441:T:C
Spleen	eqtl	1.5e-08	-0.26	3:33798622:T:C

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
35949	71.3641	1827
35953	0.4024	158
35955	0.2346	75
35954	0.0464	10
35952	0.0414	7
202718	0.0298	8
35950	0.0092	2

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.86	gold quality
nerve	UBERON:0001021	98.84	gold quality
tibial nerve	UBERON:0001323	98.84	gold quality
stromal cell of endometrium	CL:0002255	98.42	gold quality
rectum	UBERON:0001052	98.39	gold quality
colonic mucosa	UBERON:0000317	98.32	gold quality
mucosa of stomach	UBERON:0001199	98.29	gold quality
jejunal mucosa	UBERON:0000399	98.28	gold quality
skin of leg	UBERON:0001511	98.24	gold quality
monocyte	CL:0000576	98.22	gold quality
mononuclear cell	CL:0000842	98.19	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.16	gold quality
body of uterus	UBERON:0009853	98.16	gold quality
gall bladder	UBERON:0002110	98.12	gold quality
vermiform appendix	UBERON:0001154	98.08	gold quality
right lung	UBERON:0002167	98.07	gold quality
leukocyte	CL:0000738	98.04	gold quality
oral cavity	UBERON:0000167	98.04	gold quality
smooth muscle tissue	UBERON:0001135	98.04	gold quality
skin of abdomen	UBERON:0001416	98.04	gold quality
upper leg skin	UBERON:0004262	98.02	gold quality
left ovary	UBERON:0002119	98.01	gold quality
zone of skin	UBERON:0000014	97.99	gold quality
endocervix	UBERON:0000458	97.98	gold quality
ectocervix	UBERON:0012249	97.98	gold quality
esophagus mucosa	UBERON:0002469	97.96	gold quality
epithelium of nasopharynx	UBERON:0001951	97.95	gold quality
right ovary	UBERON:0002118	97.95	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.95	gold quality
right coronary artery	UBERON:0001625	97.91	gold quality
transverse colon	UBERON:0001157	97.88	gold quality
adrenal tissue	UBERON:0018303	97.86	gold quality
upper lobe of left lung	UBERON:0008952	97.79	gold quality
caecum	UBERON:0001153	97.78	gold quality
right uterine tube	UBERON:0001302	97.78	gold quality
esophagus	UBERON:0001043	97.76	gold quality
small intestine	UBERON:0002108	97.75	gold quality
bone marrow cell	CL:0002092	97.74	gold quality
pharyngeal mucosa	UBERON:0000355	97.73	gold quality
epithelium of esophagus	UBERON:0001976	97.73	gold quality
esophagus squamous epithelium	UBERON:0006920	97.71	gold quality
upper lobe of lung	UBERON:0008948	97.69	gold quality
descending thoracic aorta	UBERON:0002345	97.68	gold quality
right testis	UBERON:0004534	97.67	gold quality
left testis	UBERON:0004533	97.66	gold quality
intestine	UBERON:0000160	97.64	gold quality
thoracic aorta	UBERON:0001515	97.64	gold quality
left coronary artery	UBERON:0001626	97.63	gold quality
popliteal artery	UBERON:0002250	97.63	gold quality
tibial artery	UBERON:0007610	97.63	gold quality
aorta	UBERON:0000947	97.62	gold quality
ascending aorta	UBERON:0001496	97.62	gold quality
olfactory bulb	UBERON:0002264	97.62	gold quality
duodenum	UBERON:0002114	97.61	gold quality
large intestine	UBERON:0000059	97.58	gold quality
mucosa of transverse colon	UBERON:0004991	97.57	gold quality
colon	UBERON:0001155	97.55	gold quality
minor salivary gland	UBERON:0001830	97.54	gold quality
mouth mucosa	UBERON:0003729	97.54	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.51	gold quality
vagina	UBERON:0000996	97.50	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.48	gold quality
lower esophagus	UBERON:0013473	97.47	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.46	gold quality
tonsil	UBERON:0002372	97.45	gold quality
omental fat pad	UBERON:0010414	97.43	gold quality
peritoneum	UBERON:0002358	97.42	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.36	gold quality
mammalian vulva	UBERON:0000997	97.35	gold quality
coronary artery	UBERON:0001621	97.35	gold quality
left uterine tube	UBERON:0001303	97.34	gold quality
upper arm skin	UBERON:0004263	97.33	gold quality
lymph node	UBERON:0000029	97.31	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.25	gold quality
uterine cervix	UBERON:0000002	97.23	gold quality
stomach	UBERON:0000945	97.21	gold quality
tongue squamous epithelium	UBERON:0006919	97.21	gold quality
body of stomach	UBERON:0001161	97.20	gold quality
granulocyte	CL:0000094	97.19	gold quality
spleen	UBERON:0002106	97.17	gold quality
metanephros cortex	UBERON:0010533	97.16	gold quality
type B pancreatic cell	CL:0000169	97.11	gold quality
body of pancreas	UBERON:0001150	97.08	gold quality
lung	UBERON:0002048	97.08	gold quality
bronchial epithelial cell	CL:0002328	97.06	gold quality
islet of Langerhans	UBERON:0000006	97.05	gold quality
adipose tissue	UBERON:0001013	97.05	gold quality
squamous epithelium	UBERON:0006914	97.05	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.96	gold quality
gingiva	UBERON:0001828	96.94	gold quality
penis	UBERON:0000989	96.93	gold quality
connective tissue	UBERON:0002384	96.92	gold quality
epithelium of bronchus	UBERON:0002031	96.91	gold quality
lower esophagus mucosa	UBERON:0035834	96.90	gold quality
fundus of stomach	UBERON:0001160	96.86	gold quality
bronchus	UBERON:0002185	96.86	gold quality
ovary	UBERON:0000992	96.85	gold quality
right adrenal gland cortex	UBERON:0035827	96.82	gold quality
right adrenal gland	UBERON:0001233	96.81	gold quality
uterus	UBERON:0000995	96.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7606	no	972.31
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Spinal cord	tissue	83.2
Superior colliculi	tissue	77.2
Midbrain	tissue	74.7
Thalamus	tissue	73.0
Pons	tissue	72.5
Medulla oblongata	tissue	72.4
Substantia nigra	tissue	71.0
Periaqueductal gray	tissue	66.1
Corpus callosum	tissue	61.2
Hypothalamus	tissue	59.2
Putamen	tissue	58.6
Cerebral cortex	tissue	55.8	medium
Somatosensory cortex	tissue	55.8
Occipital cortex	tissue	55.5
Hippocampal formation	tissue	54.7
Cerebellum	tissue	54.0	low
Ventral pallidum	tissue	53.5
Septum	tissue	53.2
Motor cortex	tissue	53.0
Prefrontal cortex	tissue	52.0
Cingulate cortex	tissue	51.2
Temporal cortex	tissue	50.4
Retrosplenial cortex	tissue	50.1
Entorhinal cortex	tissue	49.5
Basal ganglia	tissue	49.4	low
Amygdala	tissue	48.3
Insular cortex	tissue	47.2
Olfactory bulb	tissue	45.2
Colon	tissue	43.6	high
Choroid plexus	tissue	40.5
Rectum	tissue	39.0	high
Parathyroid gland	tissue	38.2	high
Skin 1	tissue	37.6	high
Small intestine	tissue	36.5	high
Esophagus	tissue	36.4	high
Vagina	tissue	35.3	high
Stomach 1	tissue	35.2	high
Duodenum	tissue	34.1	high
Lung	tissue	33.2	medium
Kidney	tissue	32.7	medium
Endometrium 1	tissue	32.1	high
Thyroid gland	tissue	32.1	high
Locus coeruleus	tissue	31.5
Liver	tissue	31.1	medium
Breast	tissue	30.8	high
Smooth muscle	tissue	29.7	not detected
Placenta	tissue	29.3	medium
Cervix	tissue	29.2	high
Postcentral gyrus	tissue	29.1
Fallopian tube	tissue	29.1	high
Ovary	tissue	28.9	high
Retina	tissue	28.3
Tonsil	tissue	28.2	medium
Prostate	tissue	28.1	medium
Adipose tissue	tissue	28.0	high
Salivary gland	tissue	26.3	medium
Nucleus accumbens	tissue	26.1
Heart muscle	tissue	25.8	not detected
Epididymis	tissue	25.0	medium
Spleen	tissue	25.0	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (83.2), Dorsal spinal cord (72.6), White matter (61.2), Dorsal hippocampus (54.7), Ventral hippocampus (54.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

miRNA regulators (miRDB)

Targeting PDCD6IP by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 223 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478

Functional genomics

gnomAD constraint: pLI 0.188, LOEUF 0.583, missense Z 1.11 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000307296 splits into 5 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:33,798,729–33,812,104	114 / 106.7	1.07	no
3:33,812,105–33,825,189	47 / 83.7	0.56	no
3:33,825,190–33,838,229	242 / 250.7	0.97	no
3:33,838,230–33,864,013	266 / 390.5	0.68	no
3:33,864,014–33,866,522	202 / 205.2	0.98	no
DepMap (CRISPR cell-line fitness): dependent in 39.3% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): NCI-H2172 (-1.857), SH-SY5Y (-1.775), NCI-H510 (-1.774), NCI-H2171 (-1.746), MM1-S (-1.722), UACC-257 (-1.673), KKU-100 (-1.627), HCC-33 (-1.568), GSS (-1.543), SNU-668 (-1.496), NCI-H1355 (-1.468), HCC1143 (-1.467), COLO 201 (-1.377), COLO 792 (-1.344), EW8 (-1.343).

Literature-anchored findings (GeneRIF, showing 40)

• p95 has roles in regulating cell adhesion and morphology. (PMID:12360406)
• AIP1/Alix interacts with the apoptosis-linked protein ALG-2 and recognizes recognize the protein-protein binding motif YPXL/I, where Tyr, Pro, and Leu/Ile are crucial for its interactive properties (PMID:12588984)
• adaptor protein SETA (CIN85) and its binding partner AIP1 are involved with the cytoskeleton and in the regulation of cell adhesion (PMID:12771190)
• CHMP4b and Alix participate in formation of multivesicular bodies by cooperating with SKD1 (PMID:12860994)
• role in control of the formation of multivesicular liposomes induced by lysobisphosphatidic acid (LBPA); regulated the organization of LBPA-containing endosomes in vivo (PMID:14739459)
• The region corresponding to amino acid residues 794 to 827 in the carboxy-terminal proline-rich region of Alix is sufficient to confer the ability to interact directly with ALG2. This region includes four-tandem PxY repeats. (PMID:14999017)
• results suggest that insulin-like growth factor I receptor-induced paraptosis is mediated by MAPKs, and inhibited by AIP-1/Alix (PMID:15195070)
• Alix negatively regulates the endocytic complex containing Cbl and SETA/CIN85, and thereby antagonizes receptor endocytosis. (PMID:15456872)
• Alix is negatively regulated by Src, via direct interaction and phosphorylation. (PMID:15557335)
• Partial colocalization of FLAG-tagged Rab GTPase-activating protein-like protein and green fluorescent protein (GFP)-fused Alix was observed at cell edges (PMID:15849434)
• Alix functions in the actin-dependent intracellular positioning of endosomes (PMID:15914539)
• The HIV-1 protein Nef contributes to the release of viral particles from infected cells through its interaction with AIP1. (PMID:16764724)
• 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 microscopy. (PMID:17014699)
• Alix inhibits down-regulation of PDGFRbeta by modulating the interaction between c-Cbl and the receptor, thereby affecting the ubiquitination of the receptor (PMID:17082185)
• Alix fragment 364-716 is a potent, Alix binding site-specific inhibitor of HIV-1 assembly and release. (PMID:17158451)
• A YLDL sequence within the M protein showed L-domain activity, and its specific interaction with the N terminus of Alix/AIP1(1-211) was important for the budding of virus-like particles (VLPs) of M protein. (PMID:17166905)
• We also identified a host protein, AlP1/Alix, involved in apoptosis and efficient budding of several enveloped viruses as an interacting partner of the V and NP proteins. (PMID:17250865)
• Overexpression of the V domain inhibits HIV-1 release from cells. This inhibition of release is reversed by mutations that block binding of the Alix V domain to p6. (PMID:17277784)
• Crystal structure; ALIX serves as a flexible, extended scaffold that connects retroviral Gag proteins to ESCRT-III and other cellular-budding machinery (PMID:17350572)
• TNF-induced TRAF2-RIP1-AIP1-ASK1 complex formation and for the activation of ASK1-JNK/p38 apoptotic signaling. (PMID:17389591)
• ALIX can have a dramatic effect on HIV-1 release by binding at the CHMP4B site; the ability to use ALIX may allow HIV-1 to replicate in cells that express only low levels of Tsg101 (PMID:17428861)
• study shows that two proteins involved in HIV-1 budding-Tsg101, a subunit of the endosomal sorting complex required for transport I (ESCRT-I), & Alix, an ESCRT-associated protein-were recruited to the midbody during cytokinesis by interaction with Cep55 (PMID:17556548)
• Here, we report that dominant negative forms of Vps4A, Vps4B, and AIP1 inhibit HTLV-1 budding. (PMID:17601348)
• These results eliminate the possibility that the two transcript variants encode different isoforms of Alix protein and suggest that alternative polyadenylation is one of the mechanisms controlling Alix protein expression. (PMID:17673164)
• that ALIX and TSG101/ESCRT-I also bind a series of proteins involved in cytokinesis, including CEP55, CD2AP, ROCK1, and IQGAP1. (PMID:17853893)
• ALIX also binds to the nucleocapsid (NC) domain of HIV-1 Gag and that ALIX and its isolated Bro1 domain can be specifically packaged into viral particles via NC. (PMID:18032513)
• ALG-2-interacting protein 1 up-regulates dopamine D1 and D3 receptor expression and is important for their stability and protein trafficking. (PMID:18380665)
• Study demonstrate that formation or exposure of the p6(Gag)/p9(Gag) docking site in Alix is a regulated event and that Alix association with the membrane may play a positive role in this process. (PMID:18476810)
• C-terminal proline-rich domain of ALIX allows the access of its binding site to p6. (PMID:18477395)
• The Bro1 domain of ALIX binds specifically to C-terminal residues of the human CHMP4 proteins (CHMP4A-C). (PMID:18511562)
• the Cep55/Alix/ESCRT-III pathway has a role in cytokinesis and HIV-1 release (PMID:18641129)
• Alix down-expression decreases both LBPA levels and the lumenal vesicle content of late endosomes. Cellular cholesterol levels are also decreased, presumably because the storage capacity of endosomes is affected and thus cholesterol clearance accelerated (PMID:18644787)
• These results strongly suggest that the capacity of several mutants of Alix to block both caspase-dependent and independent cell death does not relate to their capacity to modulate autophagy. (PMID:18684393)
• Alix and ALG-2 are new actors of the TNF-R1 pathway (PMID:18936101)
• A Ca(2+)/EF3-driven arginine switch mechanism for ALG-2 binding to Alix. (PMID:18940611)
• crystal structure of the ESCRT and ALIX-binding region (EABR) of CEP55 bound to an ALIX peptide at a resolution of 2.0 angstroms; structure shows that EABR forms an aberrant dimeric parallel coiled coil (PMID:18948538)
• The native state of Alix does not have a functional Bro1 domain. (PMID:19016654)
• Results identified ALIX as an ubiquitination substrate of POSH and indicate that POSH and ALIX cooperate to facilitate efficient virus release. (PMID:19393081)
• Ca2+-loaded ALG-2 bridges Alix and TSG101 as an adaptor protein. (PMID:19520058)
• A crescent-shaped Alix dimer targets ESCRT-III CHMB4 filaments. (PMID:19523902)

Cross-species orthologs

0 orthologs

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1333753) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 50 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased brain size	2
hydrocephaly	2
increased circulating calcium level	1
domed cranium	1
abnormal stomach morphology	1
abnormal spleen morphology	1
enlarged spleen	1
enlarged lymph nodes	1
abnormal choroid plexus morphology	1
abnormal testis morphology	1
small testis	1
abnormal lung morphology	1
thick skin	1
decreased body length	1
decreased body weight	1
decreased body size	1
microphthalmia	1
decreased locomotor activity	1
increased exploration in new environment	1
increased circulating HDL cholesterol level	1
abnormal seminal vesicle morphology	1
abnormal skin morphology	1
abnormal eye morphology	1
abnormal kidney morphology	1
abnormal brain morphology	1

+25 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Rattus norvegicus	Q9QZA2	96.9%	Diamond
Mus musculus	Q9WU78	96.9%	Diamond
Canis lupus familiaris	Q8HXG3	90.1%	Diamond
Xenopus laevis	Q9W6C5	76.8%	Diamond
Caenorhabditis elegans	P34552	42.1%	Diamond
Dictyostelium discoideum	Q8T7K0	34.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PDCD6IP-DT	ncRNA	105377023
CLASP2	protein-coding	23122
LINC01811	ncRNA	101928114

Protein

Protein identifiers

Programmed cell death 6-interacting protein — Q8WUM4 (reviewed: Q8WUM4)

Alternative names: ALG-2-interacting protein 1, ALG-2-interacting protein X, Hp95

All UniProt accessions (6): Q8WUM4, A0A3B3IT07, C9IZF9, F8WBR8, F8WDK9, F8WEQ7

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional protein involved in endocytosis, multivesicular body biogenesis, membrane repair, cytokinesis, apoptosis and maintenance of tight junction integrity. Class E VPS protein involved in concentration and sorting of cargo proteins of the multivesicular body (MVB) for incorporation into intralumenal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome. Binds to the phospholipid lysobisphosphatidic acid (LBPA) which is abundant in MVBs internal membranes. The MVB pathway requires the sequential function of ESCRT-O, -I,-II and -III complexes. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis. Adapter for a subset of ESCRT-III proteins, such as CHMP4, to function at distinct membranes. Required for completion of cytokinesis. May play a role in the regulation of both apoptosis and cell proliferation. Regulates exosome biogenesis in concert with SDC1/4 and SDCBP. By interacting with F-actin, PARD3 and TJP1 secures the proper assembly and positioning of actomyosin-tight junction complex at the apical sides of adjacent epithelial cells that defines a spatial membrane domain essential for the maintenance of epithelial cell polarity and barrier. (Microbial infection) Involved in HIV-1 virus budding. Can replace TSG101 it its role of supporting HIV-1 release; this function requires the interaction with CHMP4B. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as enveloped virus budding (HIV-1 and other lentiviruses).

Subunit / interactions. Self-associates. Interacts with SH3KBP1/CIN85. Interacts with PDCD6 in a calcium -dependent manner. Interacts with TSG101 in a calcium-dependent manner; PDCD6IP homooligomerization may be required for TSG101-binding. Interacts with SGSM3. Directly interacts with CHMP4A, CHMP4B and CHMP4C. Directly interacts with CEP55 in a 1:2 stoichiometry. The interaction with CEP55 is required for PDCD6IP targeting to the midbody. May interact with PDGFRB. Interacts with SH3GL1 and SH3GL2/endophilin-1. Forms a complex with SDCBP and SDC2. Found in a complex with F-actin, TJP1/ZO-1 and PARD3. Interacts with CD2AP. Interacts with ARRDC1. Interacts (via BRO1 domain) with the ATG12-ATG3 conjugate; this interaction is bridged by ATG12 and promotes multiple PDCD6IP-mediated functions such as endolysosomal trafficking, macroautophagy and exosome biogenesis. (Microbial infection) Interacts with HIV-1 p6. Interacts with HIV-1 p9. (Microbial infection) Interacts with EIAV p9. (Microbial infection) Interacts with Murine leukemia virus Gag polyprotein (via LYPX(n)L motif). (Microbial infection) Interacts with ebola virus protein VP40 (via YPx(n)L/I motif).

Subcellular location. Cytoplasm. Cytosol. Melanosome. Cytoskeleton. Microtubule organizing center. Centrosome. Secreted. Extracellular exosome. Cell junction. Tight junction. Midbody. Midbody ring.

Post-translational modifications. May be phosphorylated on tyrosine residues by activated PDGFRB.

Disease relevance. Microcephaly 29, primary, autosomal recessive (MCPH29) [MIM:620047] A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age, sex and ethnically matched mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. MCPH29 is characterized by small head circumference apparent at birth and associated with global developmental delay, impaired intellectual development, speech delay, and behavioral abnormalities. Affected individuals also have poor overall growth with short stature, mild dysmorphic facial features, and seizures. The disease may be caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8WUM4-1	1	yes
Q8WUM4-2	2
Q8WUM4-3	3

RefSeq proteins (3): NP_001155901, NP_001243121, NP_037506* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004328	BRO1_dom	Domain
IPR025304	ALIX_V_dom	Domain
IPR038499	BRO1_sf	Homologous_superfamily

Pfam: PF03097, PF13949

UniProt features (115 total): mutagenesis site 31, helix 30, strand 11, region of interest 9, turn 8, modified residue 8, sequence variant 7, compositionally biased region 4, splice variant 3, initiator methionine 1, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

19 structures by resolution:

PDB	Title	Method	Resolution (Å)
5WA1	CHMP4C A232T in complex with ALIX BRO1	X-RAY DIFFRACTION	1.87
5V3R	CHMP4C in complex with ALIX BRO1	X-RAY DIFFRACTION	1.91
3E1R	Midbody targeting of the ESCRT machinery by a non-canonical coiled-coil in CEP55	X-RAY DIFFRACTION	2
3C3R	ALIX BRO1 CHMP4C complex	X-RAY DIFFRACTION	2.02
3C3Q	ALIX Bro1-domain:CHMIP4B co-crystal structure	X-RAY DIFFRACTION	2.1
3C3O	ALIX Bro1-domain:CHMIP4A co-crystal structure	X-RAY DIFFRACTION	2.15
2ZNE	Crystal structure of Zn2+-bound form of des3-23ALG-2 complexed with Alix ABS peptide	X-RAY DIFFRACTION	2.2
6KP3	STRUCTURE OF SENDAI VIRUS Y3/ALIX-BRO1 DOMAIN COMPLEX	X-RAY DIFFRACTION	2.2
2XS1	Crystal Structure of ALIX in complex with the SIVmac239 PYKEVTEDL Late Domain	X-RAY DIFFRACTION	2.3
2XS8	Crystal Structure of ALIX in complex with the SIVagmTan-1 AYDPARKLL Late Domain	X-RAY DIFFRACTION	2.5
2OEW	Structure of ALIX/AIP1 Bro1 Domain	X-RAY DIFFRACTION	2.55
2R05	Crystal Structure of ALIX/AIP1 in complex with the HIV-1 YPLASL Late Domain	X-RAY DIFFRACTION	2.55
2OEX	Structure of ALIX/AIP1 V Domain	X-RAY DIFFRACTION	2.58
2R03	Crystal Structure of ALIX/AIP1 in complex with the YPDL Late Domain	X-RAY DIFFRACTION	2.59
2R02	Crystal Structure of ALIX/AIP1 in complex with the HIV-1 YPLTSL Late Domain	X-RAY DIFFRACTION	2.6
3WUV	Structure basis of inactivating cell abscission with chimera peptide 2	X-RAY DIFFRACTION	2.79
2OJQ	Crystal structure of Alix V domain	X-RAY DIFFRACTION	2.87
2OEV	Crystal structure of ALIX/AIP1	X-RAY DIFFRACTION	3.3
4JJY	Alix V domain	X-RAY DIFFRACTION	6.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WUM4-F1	84.16	0.68

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins, Human disease related genes, Congenital malformations, Congenital malformations of the nervous system

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles; centrosome

Antibody reliability (HPA): IH supported · IF approved

Functional residue map

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

Post-translational modifications (8)

Type	Positions
N-acetylalanine	2
N6-acetyllysine	215
Phosphothreonine	479, 738, 741
Phosphoserine	481, 730
Omega-n-methylarginine	745

Mutagenesis-validated functional residues (31)

Position	Phenotype
199	does not support cytokinesis; loss of normal midbody formation; loss of chmp4a-, chmp4b- and chmp4c-binding in a yeast two-hybrid assay; no …
212	does not support cytokinesis; loss of normal midbody formation; loss of chmp4a-, chmp4b- and chmp4c-binding in a yeast two-hybrid assay …
216	abolishes interaction with chmp4b and abolishes rescue of ptap-type l domain-deficient hiv-1 p6.
317	diminishes rescue of ptap-type l domain-deficient hiv-1 p6.
318	greatly diminishes rescue of ptap-type l domain–deficient hiv-1 p6.
319	greatly diminishes rescue of ptap-type l domain-deficient hiv-1 p6.
319	no effect on rescue of ptap-type l domain-deficient hiv-1 p6.
495	impairs rescue of ptap-type l domain-deficient hiv-1 p6.
498	reduces interaction with hiv-1 p6 and eiav p9; abolishes rescue of ptap-type l domain-deficient hiv-1 p6.
509	abolishes interaction with hiv-1 p6; impairs rescue of ptap-type l domain-deficient hiv-1 p6.
512	no effect on interaction with hiv-1 p6; impairs rescue of ptap-type l domain-deficient hiv-1 p6.
676	loss of interaction with sdcbp.
676	abolishes interaction with hiv-1 p6 and eiav p9; abolishes rescue of ptap-type l domain-deficient hiv-1 p6; no effect on cytokinesis, nor …
680	impairs rescue of ptap-type l domain-deficient hiv-1 p6.
683	no effect on interaction with hiv-1 p6.
683	reduces interaction with hiv-1 p6 and eiav p9; abolishes rescue of ptap-type l domain-deficient hiv-1 p6.
717–720	no effect on midbody formation, nor on cytokinesis; reduced tsg101-binding; no effect on hiv-1 release. almost complete loss of …
720	abolishes interaction with tsg101; no effect on rescue of ptap-type l domain-deficient hiv-1 p6.
744–745	no effect on midbody formation; loss of cd2ap- and sh3kbp1-binding in a yeast two-hybrid assay; no effect on hiv-1 release.
757–759	no effect on midbody formation; loss of sh3gl2-binding in a yeast two-hybrid assay.
757–758	abolishes interaction with sh3gl1 and sh3gl2; no effect on rescue of ptap-type l domain-deficient hiv-1 p6.
794–813	does not support the formation of normal midbodies; loss of localization to the midbody; loss of cd2ap-, cep55-, sh3gl2-, sh3kbp1- …
800–802	abolishes interaction with cep55; inhibits support of cytokinesis.
801–802	loss of midbody localization; does not support cytokinesis; loss of cep55-binding in a yeast two-hybrid assay; no effect on hiv-1 release.
801	decreased interaction with cep55.

Function

Pathways and Gene Ontology

Reactome pathways

5 curated (TAS) of 15; 11 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

15 pathways:

ID	Pathway	Evidence
R-HSA-162588	Budding and maturation of HIV virion ⚕	curated
R-HSA-9918481	Dengue Virus-Host Interactions ⚕	curated
R-HSA-5210891	Uptake and function of anthrax toxins ⚕	curated
R-HSA-5213460	RIPK1-mediated regulated necrosis	curated
R-HSA-5675482	Regulation of necroptotic cell death	curated
R-HSA-9824439	Bacterial Infection Pathways ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-162906	HIV Infection ⚕	—
R-HSA-162587	HIV Life Cycle ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-162599	Late Phase of HIV Life Cycle ⚕	—
R-HSA-5339562	Uptake and actions of bacterial toxins ⚕	—
R-HSA-9824446	Viral Infection Pathways ⚕	—
R-HSA-5357801	Programmed Cell Death	—
R-HSA-5218859	Regulated Necrosis	—

MSigDB gene sets: 391 (showing top): GOBP_MITOTIC_CYTOKINESIS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_ENDOSOME_ORGANIZATION, GOBP_VESICLE_LOCALIZATION, GNF2_BNIP2, PAL_PRMT5_TARGETS_UP, GOBP_VESICLE_ORGANIZATION, GOBP_CHROMOSOME_LOCALIZATION, GOBP_APICAL_JUNCTION_ASSEMBLY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_REGULATION_OF_EXOCYTOSIS

GO Biological Process (19): mitotic cytokinesis (GO:0000281), actomyosin contractile ring assembly (GO:0000915), apoptotic process (GO:0006915), regulation of centrosome duplication (GO:0010824), protein transport (GO:0015031), macroautophagy (GO:0016236), multivesicular body assembly (GO:0036258), viral budding via host ESCRT complex (GO:0039702), maintenance of epithelial cell apical/basal polarity (GO:0045199), viral budding (GO:0046755), protein homooligomerization (GO:0051260), midbody abscission (GO:0061952), bicellular tight junction assembly (GO:0070830), regulation of membrane permeability (GO:0090559), extracellular exosome biogenesis (GO:0097734), positive regulation of exosomal secretion (GO:1903543), regulation of extracellular exosome assembly (GO:1903551), positive regulation of extracellular exosome assembly (GO:1903553), cell division (GO:0051301)

GO Molecular Function (4): proteinase activated receptor binding (GO:0031871), protein homodimerization activity (GO:0042803), calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515)

GO Cellular Component (15): immunological synapse (GO:0001772), endosome (GO:0005768), centrosome (GO:0005813), cytosol (GO:0005829), bicellular tight junction (GO:0005923), focal adhesion (GO:0005925), membrane (GO:0016020), melanosome (GO:0042470), actomyosin (GO:0042641), extracellular exosome (GO:0070062), endoplasmic reticulum exit site (GO:0070971), Flemming body (GO:0090543), extracellular vesicle (GO:1903561), extracellular region (GO:0005576), cytoplasm (GO:0005737)

Reactome top-level categories

12 top-level categories:

Category	Pathways
Infectious disease	2
Late Phase of HIV Life Cycle	1
Uptake and actions of bacterial toxins	1
Regulated Necrosis	1
RIPK1-mediated regulated necrosis	1
Dengue Virus Infection	1
HIV Infection	1
HIV Life Cycle	1
Viral Infection Pathways	1
Programmed Cell Death	1
Bacterial Infection Pathways	1
Disease	1

GO top-level categories

showing 60 of 63 GO namespaces:

Category	Terms
cellular anatomical structure	8
extracellular exosome assembly	2
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
assembly of actomyosin apparatus involved in cytokinesis	1
actomyosin contractile ring organization	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
regulation of centrosome cycle	1
centrosome duplication	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
autophagosome assembly	1
autophagy	1
multivesicular body organization	1
organelle assembly	1
viral budding	1
maintenance of apical/basal cell polarity	1
establishment or maintenance of epithelial cell apical/basal polarity	1
viral process	1
virion assembly	1
protein complex oligomerization	1
membrane organization	1
mitotic cytokinetic process	1
apical junction assembly	1
tight junction assembly	1
regulation of biological quality	1
extracellular vesicle biogenesis	1
positive regulation of cellular component biogenesis	1
positive regulation of exocytosis	1
regulation of exosomal secretion	1
exosomal secretion	1
regulation of organelle assembly	1
positive regulation of organelle assembly	1
regulation of extracellular exosome assembly	1
cellular process	1
G protein-coupled receptor binding	1
identical protein binding	1
protein dimerization activity	1
calcium ion binding	1
protein binding	1
binding	1
plasma membrane	1
endomembrane system	1
cytoplasmic vesicle	1
centriole	1
microtubule organizing center	1
cytoplasm	1
apical junction complex	1
tight junction	1
cell-substrate junction	1
pigment granule	1
actin cytoskeleton	1
extracellular vesicle	1
endoplasmic reticulum	1
midbody	1
extracellular region	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 20 of 39 annotations. The rest are phylogenetic / computational / electronic (IEA).

20 experimentally-supported GO terms:

GO term	NS	Evidence
midbody abscission	BP	mutant phenotype
mitotic cytokinesis	BP	direct assay
positive regulation of exosomal secretion	BP	mutant phenotype
positive regulation of extracellular exosome assembly	BP	mutant phenotype
protein homooligomerization	BP	direct assay
regulation of centrosome duplication	BP	mutant phenotype
regulation of extracellular exosome assembly	BP	mutant phenotype
viral budding	BP	direct assay
viral budding via host ESCRT complex	BP	genetic interaction
Flemming body	CC	direct assay
centrosome	CC	direct assay
endoplasmic reticulum exit site	CC	mutant phenotype
extracellular exosome	CC	direct assay
extracellular vesicle	CC	high-throughput assay
focal adhesion	CC	high-throughput assay
immunological synapse	CC	direct assay
membrane	CC	high-throughput assay
calcium-dependent protein binding	MF	physical interaction
protein homodimerization activity	MF	physical interaction
proteinase activated receptor binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,651 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDCD6IP	TSG101	Q99816	930
PDCD6IP	CHMP4A	Q9BY43	892
PDCD6IP	PDCD6	O75340	890
PDCD6IP	VPS4B	O75351	861
PDCD6IP	CHMP4C	Q96CF2	850
PDCD6IP	VPS4A	Q9UN37	845
PDCD6IP	CHMP6	Q96FZ7	784
PDCD6IP	CEP55	Q53EZ4	767
PDCD6IP	CD81	P18582	763
PDCD6IP	CD63	P08962	734
PDCD6IP	CD9	P21926	733
PDCD6IP	CHMP2A	O43633	709
PDCD6IP	VPS25	Q9BRG1	692
PDCD6IP	SDCBP	O00560	679
PDCD6IP	CHMP1A	Q9HD42	670

IntAct

Human interaction partners of PDCD6IP in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 46 partners by confidence:

Partner	Interaction type	MIscore	Records
CEP55	physical association	0.960	17
PDCD6	association	0.900	11
CHMP4B	direct interaction	0.860	5
HCK	physical association	0.710	4
EGFR	physical association	0.680	4
CHMP4A	direct interaction	0.680	3
FYN	physical association	0.670	6
CHMP4C	direct interaction	0.670	3
SRC	physical association	0.650	7
TSG101	physical association	0.610	2
SH3KBP1	physical association	0.590	5
SH3GL1	physical association	0.590	4
CD2AP	physical association	0.570	3
GRB2	physical association	0.550	2
LGALS3	direct interaction	0.530	2
SDCBP	colocalization	0.440	2
GABARAP	direct interaction	0.440	1
GABARAPL1	direct interaction	0.440	1
GABARAPL2	direct interaction	0.440	1
LRRN1	direct interaction	0.440	1
MAP1LC3C	direct interaction	0.440	1
NUP155	direct interaction	0.440	1
SDCBP2	direct interaction	0.440	1
PTK2B	physical association	0.400	1
YES1	physical association	0.400	1
CXCR1	physical association	0.370	1
KEAP1	physical association	0.370	1
MAPK6	physical association	0.370	1
PLXNA2	physical association	0.370	1
RNF11	physical association	0.370	1

BioGRID (422 interactions; top human partners by supporting records): TSG101 (Reconstituted Complex; 17 records), CEP55 (Two-hybrid; 12 records), CHMP4B (Affinity Capture-MS; 9 records), PDCD6 (Affinity Capture-MS; 9 records), SH3KBP1 (Reconstituted Complex; 9 records), ALG2 (Two-hybrid; 8 records), EGFR (Two-hybrid; 6 records), CHMP4A (Two-hybrid; 5 records), SRC (Biochemical Activity; 5 records), UBC (Reconstituted Complex; 5 records), DRD3 (Two-hybrid; 4 records), F2R (Affinity Capture-Western; 4 records), SH3GL2 (Affinity Capture-Western; 4 records), ACE2 (Proximity Label-MS; 3 records), ARRDC1 (Reconstituted Complex; 3 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
SRC	“down-regulates activity”	PDCD6IP	phosphorylation

Protein complexes (CORUM) (7)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

7 complexes by size:

Complex	Subunits	Members
MVB12B-PDCD6-PDCD6IP-TSG101-VPS28-VPS37A complex	6	MVB12B, PDCD6, PDCD6IP, TSG101, VPS28, VPS37A
MVB12B-PDCD6-PDCD6IP-TSG101-VPS28-VPS37B complex	6	PDCD6, PDCD6IP, TSG101, VPS28, VPS37B, MVB12B
MVB12B-PDCD6-PDCD6IP-TSG101-VPS28-VPS37C complex	6	VPS37C, MVB12B, PDCD6, PDCD6IP, TSG101, VPS28
MVB12B-PDCD6-PDCD6IP-TSG101-VPS28-VPS37D complex	6	VPS28, VPS37D, MVB12B, PDCD6, PDCD6IP, TSG101
CD63-PDCD6IP-SDCBP complex	3	SDCBP, CD63, PDCD6IP
PDCD6IP-SDCBP-SDC1 complex	3	PDCD6IP, SDC1, SDCBP
CAV1-OCLN-PDCD6IP complex	3	PDCD6IP, CAV1, OCLN

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 46 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
Budding and maturation of HIV virion	5	55.1×	4e-06
Endosomal Sorting Complex Required For Transport (ESCRT)	5	49.8×	4e-06
EGFR downregulation	5	46.8×	4e-06
Signaling by CSF1 (M-CSF) in myeloid cells	5	46.8×	4e-06
Signaling by EGFR	5	44.1×	4e-06
FCGR3A-mediated phagocytosis	5	25.3×	4e-05
Macroautophagy	7	21.8×	4e-06
HCMV Late Events	6	16.0×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
viral budding via host ESCRT complex	5	87.2×	4e-07
midbody abscission	5	79.6×	5e-07
autophagosome maturation	9	68.7×	3e-12
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	5	59.1×	2e-06
multivesicular body assembly	5	57.2×	2e-06
membrane fission	5	44.7×	5e-06
macroautophagy	7	36.6×	2e-07
autophagy	5	12.0×	9e-04

Disease & clinical

Genetic variants

Variant evidence for PDCD6IP: 143 ClinVar records (1 pathogenic / likely pathogenic); 8 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	97
Likely benign	5
Benign	5

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1706482	NM_013374.6(PDCD6IP):c.154_158dup (p.Val54fs)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore PDCD6IP’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 1,402):

Position(s)	Effect	Δscore	Sites
3:33813549	acceptor_gain	1.0000
3:33813554	acceptor_gain	1.0000
3:33813557–33813558	acceptor_loss	1.0000	2
3:33821944	acceptor_gain	1.0000
3:33821952	acceptor_gain	1.0000
3:33821953–33821954	acceptor_loss	1.0000	6
3:33822083–33822084	donor_loss	1.0000	4
3:33825185–33825186	acceptor_loss	1.0000	5
3:33825238	acceptor_gain	1.0000
3:33825341–33825342	donor_loss	1.0000	5

AlphaMissense

2,425 missense substitutions predicted likely pathogenic (of 5,656 scored), across 665 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M191	9	0.863	0.991
D693	8	0.997	0.999
N315	8	0.996	1.000
D178	8	0.995	0.999
D314	8	0.994	0.999
D465	8	0.989	0.999
F105	8	0.983	0.996
F355	8	0.982	0.997
H320	8	0.981	0.999
D97	8	0.979	0.996
D73	8	0.975	0.995
F696	8	0.973	0.999
F99	8	0.972	0.995
F676	8	0.970	1.000
F93	8	0.969	0.998
F317	8	0.959	0.997
D506	8	0.958	0.984
F584	8	0.942	0.998
D353	8	0.940	0.988
D316	8	0.937	0.991

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.88e-06

Disease associations

OMIM: gene MIM:608074 | disease phenotypes: MIM:620047

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
microcephaly 29, primary, autosomal recessive	Strong	Autosomal recessive	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Fetal anomalies	amber
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Paediatric disorders	amber
Severe microcephaly	amber

Mondo (1): microcephaly 29, primary, autosomal recessive (MONDO:0031060)

HPO phenotypes

35 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000122	Unilateral renal agenesis
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000307	Pointed chin
HP:0000340	Sloping forehead
HP:0000348	High forehead
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000574	Thick eyebrow
HP:0000582	Upslanted palpebral fissure
HP:0000712	Emotional lability
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001302	Pachygyria
HP:0001347	Hyperreflexia
HP:0001510	Growth delay
HP:0002119	Ventriculomegaly
HP:0002282	Gray matter heterotopia
HP:0003103	Abnormal cortical bone morphology
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0004719	Hyperechogenic kidneys
HP:0005326	Hypoplastic philtrum
HP:0005565	Reduced renal corticomedullary differentiation
HP:0007333	Hypoplasia of the frontal lobes
HP:0009879	Simplified gyral pattern
HP:0010864	Severe intellectual disability
HP:0011451	Primary microcephaly
HP:0012081	Enlarged cerebellum

GWAS associations

8 associations:

Study	Trait	p-value
GCST007327_207	Smoking status (ever vs never smokers)	4e-12
GCST003123_8	Severe influenza A (H1N1) infection	2e-8
GCST003770_70	Neuroticism	2e-8
GCST004250_39	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	9e-7
GCST001523_3	Visceral adipose tissue adjusted for BMI	3e-6
GCST005790_89	Rosacea symptom severity	3e-6
GCST002127_30	Periodontitis (Mean PAL)	4e-6
GCST008969_6	White coat effect (clinic diastolic blood pressure minus ambulatory diastolic blood pressure)	8e-6

EFO canonical traits (from GWAS)

7 canonical traits:

EFO ID	Trait name
EFO:0004340	body mass index
EFO:1001488	influenza A (H1N1)
EFO:0007660	neuroticism measurement
EFO:0007965	response to combination chemotherapy
EFO:0009180	rosacea severity measurement
EFO:0004318	smoking behavior
EFO:0006945	diastolic blood pressure change measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725177 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (3 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.37	Kd	4239	nM	CHEMBL5653589
5.37	ED50	4239	nM	CHEMBL5653589
5.31	Kd	4910	nM	CHEMBL3752910
5.31	ED50	4910	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 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-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148956: Binding affinity to human PDCD6IP human incubated for 45 mins by Kinobead based pull down assay	kd	4.2386	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148956: Binding affinity to human PDCD6IP human incubated for 45 mins by Kinobead based pull down assay	kd	4.9097	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases expression, decreases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Rotenone	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression, affects expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
epimedokoreanin B	decreases expression	1
beauvericin	increases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
uranyl acetate	affects expression	1
honokiol	decreases expression	1
bisphenol A	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
hesperetin	decreases expression, decreases reaction	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
morusin	decreases expression, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
azoxystrobin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
pyrachlostrobin	decreases expression	1
bromovanin	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651998	Binding	Binding affinity to human PDCD6IP human incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1BA	Abcam HEK293 PDCD6IP KO	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PDCD6IP across ~30M SureChEMBL compounds — explore on Sugi Predict.