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): 142 total — 1 pathogenic
• Phenotypes (HPO): 35
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 39.3% of screened cell lines
• 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: 27 — 12 protein_coding, 6 retained_intron, 5 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

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

RefSeq mRNA: 2 — MANE Select: NM_013374 NM_001162429, 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.

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

295 total, 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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

miRNA regulators (miRDB)

223 targeting PDCD6IP, 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-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

DepMap (CRISPR cell-line fitness): dependent in 39.3% of screened cell lines.

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

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 stoechiometry. 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 (2): NP_001155901, 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 (109 total): mutagenesis site 31, helix 24, 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.

PDB	Method	Resolution (Å)
5WA1	X-RAY DIFFRACTION	1.87
5V3R	X-RAY DIFFRACTION	1.91
3E1R	X-RAY DIFFRACTION	2
3C3R	X-RAY DIFFRACTION	2.02
3C3Q	X-RAY DIFFRACTION	2.1
3C3O	X-RAY DIFFRACTION	2.15
2ZNE	X-RAY DIFFRACTION	2.2
6KP3	X-RAY DIFFRACTION	2.2
2XS1	X-RAY DIFFRACTION	2.3
2XS8	X-RAY DIFFRACTION	2.5
2OEW	X-RAY DIFFRACTION	2.55
2R05	X-RAY DIFFRACTION	2.55
2OEX	X-RAY DIFFRACTION	2.58
2R03	X-RAY DIFFRACTION	2.59
2R02	X-RAY DIFFRACTION	2.6
3WUV	X-RAY DIFFRACTION	2.79
2OJQ	X-RAY DIFFRACTION	2.87
2OEV	X-RAY DIFFRACTION	3.3
4JJY	X-RAY DIFFRACTION	6.5

Predicted structure (AlphaFold)

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

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): 2, 215, 479, 481, 730, 738, 741, 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 t
212	does not support cytokinesis; loss of normal midbody formation; loss of chmp4a-, chmp4b- and chmp4c-binding in a yeast t
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
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
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 relea
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-
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
801	decreased interaction with cep55.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-162588	Budding and maturation of HIV virion
R-HSA-5210891	Uptake and function of anthrax toxins
R-HSA-5213460	RIPK1-mediated regulated necrosis
R-HSA-5675482	Regulation of necroptotic cell death
R-HSA-9918481	Dengue Virus-Host Interactions

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 (20): 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), obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway (GO:0090611), 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 (17): 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), cytoskeleton (GO:0005856), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
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

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

1882 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDCD6IP	PDCD6	O75340	998
PDCD6IP	TSG101	Q99816	997
PDCD6IP	CHMP4A	Q9BY43	996
PDCD6IP	SDCBP	O00560	980
PDCD6IP	CEP55	Q53EZ4	924
PDCD6IP	VPS4B	O75351	922
PDCD6IP	CHMP4C	Q96CF2	887
PDCD6IP	SDC1	P18827	860
PDCD6IP	VPS4A	Q9UN37	855
PDCD6IP	CD63	P08962	837
PDCD6IP	CHMP2A	O43633	811
PDCD6IP	CD9	P21926	809
PDCD6IP	CD81	P18582	803
PDCD6IP	VTA1	Q9NP79	796
PDCD6IP	CHMP6	Q96FZ7	790

IntAct

277 interactions, top by confidence:

A	B	Type	Score
PDCD6IP	CEP55	psi-mi:“MI:0915”(physical association)	0.960
CEP55	PDCD6IP	psi-mi:“MI:0915”(physical association)	0.960
CEP55	PDCD6IP	psi-mi:“MI:0407”(direct interaction)	0.960
PDCD6IP	CEP55	psi-mi:“MI:0914”(association)	0.960
PDCD6IP	PDCD6	psi-mi:“MI:0914”(association)	0.900
PDCD6	PDCD6IP	psi-mi:“MI:0407”(direct interaction)	0.900
PDCD6	PDCD6IP	psi-mi:“MI:0915”(physical association)	0.900
PDCD6IP	PDCD6	psi-mi:“MI:0915”(physical association)	0.900
CHMP4B	PDCD6IP	psi-mi:“MI:0407”(direct interaction)	0.860
PDCD6IP	CHMP4B	psi-mi:“MI:0407”(direct interaction)	0.860
PDCD6IP	CHMP4B	psi-mi:“MI:0915”(physical association)	0.860
PDCD6	SEC31A	psi-mi:“MI:0403”(colocalization)	0.740
PDCD6	SEC31A	psi-mi:“MI:0914”(association)	0.740
CEP55	TEX14	psi-mi:“MI:0915”(physical association)	0.720
PDCD6IP	gag	psi-mi:“MI:0407”(direct interaction)	0.710
gag	PDCD6IP	psi-mi:“MI:0915”(physical association)	0.710

BioGRID (416): PDCD6IP (Reconstituted Complex), CEP55 (Two-hybrid), PDCD6IP (Affinity Capture-Western), PDCD6IP (Two-hybrid), SDCBP (Reconstituted Complex), PDCD6IP (Affinity Capture-MS), PDCD6IP (Affinity Capture-MS), PDCD6IP (Two-hybrid), ENO1 (Co-fractionation), ESD (Co-fractionation), GOT1 (Co-fractionation), MIF (Co-fractionation), PDCD6IP (Co-fractionation), PDCD6IP (Co-fractionation), PDCD6IP (Co-fractionation)

ESM2 similar proteins: A3KQV2, A4IIL4, O00471, O54921, P48553, P62944, P63009, P63010, P79020, P97878, Q00004, Q0IIZ5, Q1L8F9, Q29RF7, Q3SYS9, Q3TLI0, Q3TPX4, Q498H0, Q4G074, Q4QR29, Q4V8K5, Q4VA53, Q5F3K0, Q5KU05, Q5R6J0, Q5RDD7, Q5VW32, Q5VYK3, Q62018, Q6DDM4, Q6DEU9, Q6IR80, Q6P1I3, Q6PD62, Q6PDI5, Q6TRW4, Q6ZPU9, Q8BMA6, Q8K2Q7, Q8WUM4

Diamond homologs: P34552, Q8TCX5, Q8WUM4, Q9QZA2, Q9W6C5, Q9WU78, A4D2P6, A4FUC9, A5PKA5, A8MT19, C8V212, F4HXZ1, O08774, O13783, O14924, O15085, P0CM44, P0CM45, P48582, P49796, P49797, Q0QWG9, Q28619, Q3SX40, Q3T0X8, Q3UHD6, Q4IBS9, Q4PHA8, Q4X0Z5, Q5AJC1, Q5RCF7, Q5T2W1, Q5ZM14, Q61085, Q63ZR5, Q6BRL3, Q6CGJ5, Q6DJJ6, Q6P0Q8, Q6PB44

SIGNOR signaling

1 interactions.

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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 164 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
Endosomal Sorting Complex Required For Transport (ESCRT)	6	21.5×	1e-04
Budding and maturation of HIV virion	5	19.8×	8e-04
Late endosomal microautophagy	6	19.0×	1e-04
EGFR downregulation	5	16.8×	1e-03
Macroautophagy	9	10.1×	1e-04
RHOQ GTPase cycle	5	8.8×	1e-02
HCMV Late Events	8	7.7×	1e-03
L1CAM interactions	6	7.0×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
viral budding via host ESCRT complex	5	29.9×	8e-05
autophagosome maturation	11	28.8×	1e-10
multivesicular body assembly	6	23.6×	3e-05
membrane fission	7	21.5×	8e-06
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	5	20.3×	5e-04
macroautophagy	9	16.2×	2e-06
mitophagy	6	14.2×	5e-04
endoplasmic reticulum to Golgi vesicle-mediated transport	10	10.1×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	97
Likely benign	4
Benign	5

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1706482	NM_013374.6(PDCD6IP):c.154_158dup (p.Val54fs)	Pathogenic

SpliceAI

2713 predictions. Top by Δscore:

Variant	Effect	Δscore
3:33813548:A:AG	acceptor_gain	1.0000
3:33813549:T:G	acceptor_gain	1.0000
3:33813553:A:AG	acceptor_gain	1.0000
3:33813554:T:G	acceptor_gain	1.0000
3:33813555:CCAGA:C	acceptor_loss	1.0000
3:33813556:CAGAT:C	acceptor_loss	1.0000
3:33813557:A:AC	acceptor_loss	1.0000
3:33813557:A:AG	acceptor_gain	1.0000
3:33813558:G:GA	acceptor_gain	1.0000
3:33813558:GATCT:G	acceptor_gain	1.0000
3:33813627:GG:G	donor_gain	1.0000
3:33813628:GG:G	donor_gain	1.0000
3:33813629:G:GG	donor_gain	1.0000
3:33821943:A:AG	acceptor_gain	1.0000
3:33821944:A:AG	acceptor_gain	1.0000
3:33821950:TACAG:T	acceptor_loss	1.0000
3:33821952:C:G	acceptor_gain	1.0000
3:33821953:A:AG	acceptor_gain	1.0000
3:33821953:AGCTC:A	acceptor_loss	1.0000
3:33821954:G:GC	acceptor_gain	1.0000
3:33821954:GC:G	acceptor_gain	1.0000
3:33821954:GCT:G	acceptor_gain	1.0000
3:33821954:GCTC:G	acceptor_gain	1.0000
3:33821954:GCTCT:G	acceptor_gain	1.0000
3:33822079:CCAGG:C	donor_loss	1.0000
3:33822080:CAGG:C	donor_loss	1.0000
3:33822081:AGGT:A	donor_loss	1.0000
3:33822082:GGTA:G	donor_loss	1.0000
3:33822083:GT:G	donor_loss	1.0000
3:33822084:T:G	donor_loss	1.0000

AlphaMissense

5656 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:33813577:T:A	W95R	1.000
3:33813577:T:C	W95R	1.000
3:33822014:A:C	S132R	1.000
3:33822016:C:A	S132R	1.000
3:33822016:C:G	S132R	1.000
3:33825332:C:A	A203D	1.000
3:33826504:C:A	A214D	1.000
3:33836154:T:A	N315K	1.000
3:33836154:T:G	N315K	1.000
3:33836162:T:A	I318N	1.000
3:33836164:T:G	Y319D	1.000
3:33841917:T:C	L401P	1.000
3:33844178:T:A	W476R	1.000
3:33844178:T:C	W476R	1.000
3:33844180:G:C	W476C	1.000
3:33844180:G:T	W476C	1.000
3:33844194:C:T	S481F	1.000
3:33855166:T:C	F676L	1.000
3:33855168:T:A	F676L	1.000
3:33855168:T:G	F676L	1.000
3:33855233:G:C	R698P	1.000
3:33855254:T:C	L705P	1.000
3:33798758:A:C	K10N	0.999
3:33798758:A:T	K10N	0.999
3:33798865:T:C	L46P	0.999
3:33798876:C:A	R50S	0.999
3:33813579:G:C	W95C	0.999
3:33813579:G:T	W95C	0.999
3:33821985:G:A	C122Y	0.999
3:33821986:T:G	C122W	0.999

dbSNP variants (sampled 300 via entrez): RS1000038613 (3:33827957 A>C), RS1000105852 (3:33834466 A>G), RS1000150528 (3:33835545 G>A), RS1000204860 (3:33835042 C>T), RS1000348510 (3:33840251 A>G), RS1000365721 (3:33847106 G>A,C), RS1000375829 (3:33820710 T>G), RS1000411395 (3:33863980 A>G), RS1000424831 (3:33846473 A>G,T), RS1000571056 (3:33832804 T>C), RS1000645771 (3:33834230 G>A), RS1000679834 (3:33838780 A>ATATATATATT), RS1000688972 (3:33865837 G>A), RS1000714686 (3:33796731 G>A), RS1000761181 (3:33864380 A>G)

Disease associations

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

GenCC curated gene-disease

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

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

Orphanet (0):

HPO phenotypes

35 total (30 of 35 shown, 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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001523_3	Visceral adipose tissue adjusted for BMI	3.000000e-06
GCST002127_33	Periodontitis (Mean PAL)	4.000000e-06
GCST003123_8	Severe influenza A (H1N1) infection	2.000000e-08
GCST003770_84	Neuroticism	2.000000e-08
GCST004250_12	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	9.000000e-07
GCST005790_89	Rosacea symptom severity	3.000000e-06
GCST007327_182	Smoking status (ever vs never smokers)	4.000000e-12
GCST008969_6	White coat effect (clinic diastolic blood pressure minus ambulatory diastolic blood pressure)	8.000000e-06

EFO canonical traits (7, from GWAS)

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 (VIP=true, CPIC=false)

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	affects cotreatment, increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Rotenone	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases 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)

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