PDCD6IP programmed cell death 6 interacting protein [Homo sapiens (human)] - Gene

Summary

Official Symbol: PDCD6IPprovided by HGNC
Official Full Name: programmed cell death 6 interacting proteinprovided by HGNC
Primary source: HGNC:HGNC:8766
See related: Ensembl:ENSG00000170248 MIM:608074; AllianceGenome:HGNC:8766
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: AIP1; ALIX; HP95; DRIP4; MCPH29
Summary: 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. [provided by RefSeq, Jan 2012]
Expression: Ubiquitous expression in colon (RPKM 28.2), esophagus (RPKM 23.0) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 3p22.3

Exon count:: 19

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	3	NC_000003.12 (33798630..33869703)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	3	NC_060927.1 (33799362..33870437)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	3	NC_000003.11 (33840122..33911195)

Chromosome 3 - NC_000003.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer.
Title: SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer.
ALIX promotes cell migration and invasion of head and neck squamous cell carcinoma by regulating the expression of MMP9, MMP14, VEGF-C.
Title: ALIX promotes cell migration and invasion of head and neck squamous cell carcinoma by regulating the expression of MMP9, MMP14, VEGF-C.
miR3633p attenuates the oxygenglucose deprivation/reoxygenationinduced neuronal injury in vitro by targeting PDCD6IP.
Title: miR‑363‑3p attenuates the oxygen‑glucose deprivation/reoxygenation‑induced neuronal injury in vitro by targeting PDCD6IP.
Roles of ESCRT Proteins ALIX and CHMP4A and Their Interplay with Interferon-Stimulated Gene 15 during Tick-Borne Flavivirus Infection.
Title: Roles of ESCRT Proteins ALIX and CHMP4A and Their Interplay with Interferon-Stimulated Gene 15 during Tick-Borne Flavivirus Infection.
Mechanistic roles of tyrosine phosphorylation in reversible amyloids, autoinhibition, and endosomal membrane association of ALIX.
Title: Mechanistic roles of tyrosine phosphorylation in reversible amyloids, autoinhibition, and endosomal membrane association of ALIX.
Structural Insight into the Interaction of Sendai Virus C Protein with Alix To Stimulate Viral Budding.
Title: Structural Insight into the Interaction of Sendai Virus C Protein with Alix To Stimulate Viral Budding.
PDCD6IP, encoding a regulator of the ESCRT complex, is mutated in microcephaly.
Title: PDCD6IP, encoding a regulator of the ESCRT complex, is mutated in microcephaly.
Occludin, caveolin-1, and Alix form a multi-protein complex and regulate HIV-1 infection of brain pericytes.
Title: Occludin, caveolin-1, and Alix form a multi-protein complex and regulate HIV-1 infection of brain pericytes.
ESCRT-III controls nuclear envelope deformation induced by progerin.
Title: ESCRT-III controls nuclear envelope deformation induced by progerin.
Alix and Syntenin-1 direct amyloid precursor protein trafficking into extracellular vesicles.
Title: Alix and Syntenin-1 direct amyloid precursor protein trafficking into extracellular vesicles.

Submit: New GeneRIF Correction See all GeneRIFs (115)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Microcephaly 29, primary, autosomal recessive MedGen: C5774220 OMIM: 620047 GeneReviews: Not available	not available

EBI GWAS Catalog

Description
Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study of chronic periodontitis in a general German population. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Replication interactions

Interaction	Pubs
HIV-1 incorporates PDCD6IP (ALIX) and TSG101 into virions, which is sensitive to mutations in YP and PTAP domains respectively	PubMed
HIV-1 replication, specifically budding, requires PDCD6IP (ALIX) as shown through shRNA knockdown in HEK293T cells	PubMed
Knockdown of programmed cell death 6 interacting protein (AIP1, ALIX) by siRNA inhibits HIV-1 release and infectivity	PubMed

Protein interactions

Protein	Gene	Interaction	Pubs
Envelope surface glycoprotein gp160, precursor	env	In the absence of Vpu, Env accumulates extensively within clathrin-coated endosomal structures, including the viral proteins Gag and MA; the tetraspanins CD63 and CD81; the adaptor protein complex AP-3; and AIP1/ALIX, a cellular cofactor for viral budding	PubMed
Nef	nef	HIV-1 Nef-mediated CD4 degradation requires ALIX and interaction of Nef with ALIX in endosomes that contain CD4	PubMed
	nef	HIV-1 Nef interacts with ALIX in late endosomes, and Bro1 (residues 1-360) and V (residues 360-717) domains of ALIX are required for this interaction with Nef	PubMed
	nef	Residues 135-138 of HIV-1 Nef bind to AIP1 in vitro and in cells; the binding between Nef and AIP1 is required for formation of multivesicular bodies (MVBs) and contributes to the egress of viral particles from infected cells	PubMed
	nef	HIV-1 Nef increases the production of exosomes and co-localizes with exosomal proteins CD63, AIP/Alix, AChE, Hsc70, LAMP2, and annexin A2 in HeLa cells	PubMed
Pr55(Gag)	gag	HIV-1 NC-mediated incorporation of ALIX into virions requires the zinc fingers of NC and the Bro1 domain of ALIX	PubMed
	gag	Superresolution imaging of HIV-1 Gag and ESCRT proteins (TSG101, ALIX, CHMP4B, and CHMP4C) demonstrates in HeLa cells that Gag assemblages often has ESCRT proteins in their direct vicinity	PubMed
	gag	Galectin-3 co-localizes with HIV-1 Gag and Alix, and facilitates the association of Gag with Alix in cells	PubMed
	gag	Incorporation of ALIX into HIV-1 virus-like particles is dependent on the Gag late domains	PubMed
	gag	ALIX recruitment to both HIV-1 and EIAV Gag is transient at the end of Gag polymerization and the HIV-1 and EIAV profiles are only different in terms of the retention level of ALIX within the virus-like particles	PubMed
	gag	The Bro1 domain of Alix inhibits HIV budding by targeting both PTAP/TSG101 and LYPXnL/Alix pathways. The NC domain of Gag is the primary target for Bro1 inhibition by Gag-mediated recruitment of Bro1 to the plasma membrane	PubMed
	gag	The S40F mutation in HIV-1 p6 enhances ALIX binding to HIV-1 Gag in the yeast two-hybrid assay. The Y36S mutation introduced into the S40F mutant disrupts ALIX interaction with Gag and restores spherical particle formation in cells	PubMed
	gag	Fusion protein Dub-Alix, the catalytic domain of the Herpes Simplex UL36 deubiquitinating enzyme (DUb) fused onto Alix, inhibits HIV-1 release, which involves the interaction between HIV-1 Gag and Alix	PubMed
	gag	In the absence of Vpu, Env accumulates extensively within clathrin-coated endosomal structures, including the viral proteins Gag and MA; the tetraspanins CD63 and CD81; the adaptor protein complex AP-3; and AIP1/ALIX, a cellular cofactor for viral budding	PubMed
	gag	Alix-mediated rescue of HIV-1 PTAP(-) release requires interaction with Nedd4-1. Ubiquitinated Alix is incorporated into HIV-1 PTAP(-) rescued particles	PubMed
	gag	Phe105 loop (residues 99-112) in the Bro1 domain of Alix is required for efficient Alix-mediated HIV-1 release. The disruption of the Phe105 loop interferes with its ability to interact with HIV-1 Gag	PubMed
	gag	Recruitment of CHMP4B by ALIX to HIV-1 Gag puncta is observed in in-vitro membrane model	PubMed
	gag	ALIX proteins with point mutations (Val498Asp, Phe676Asp, and Ile683Asp) that inhibit the p6 36YPLASL41 binding fail to rescue HIV-1 deltaPTAP release or infectivity	PubMed
	gag	Overexpression of AIP1(364-716) severely disrupts Gag processing, resulting in an increase in the ratio of Gag to p25/p24	PubMed
	gag	A single amino acid Phe676 of Alix is at the center of a large hydrophobic pocket and is crucial for binding to HIV-1 p6	PubMed
	gag	Overexpression of AIP1(364-716) leads to a reduction in the cell-associated levels of HIV-1 Gag	PubMed
matrix	gag	In the absence of Vpu, Env accumulates extensively within clathrin-coated endosomal structures, including the viral proteins Gag and MA; the tetraspanins CD63 and CD81; the adaptor protein complex AP-3; and AIP1/ALIX, a cellular cofactor for viral budding	PubMed
nucleocapsid	gag	HIV-1 NC-mediated incorporation of ALIX into virions requires the zinc fingers of NC and the Bro1 domain of ALIX	PubMed
	gag	The N-terminal Bro1 domain (Brox) of ALIX bind to HIV-1 NC. Unexpectedly, Brox retains significant activity even if its CHMP4 binding site is disrupted	PubMed
	gag	Residues Q8, K11, K48, R51, R56, and K60 are part of the Bro1 domain of ALIX binding to HIV-1 NC, which involves RNA. Disruption of the Bro1-NC binding inhibits ALIX function in virus release	PubMed
	gag	The Bro1 domain of Alix inhibits HIV budding by targeting both PTAP/TSG101 and LYPXnL/Alix pathways. The NC domain of Gag is the primary target for Bro1 inhibition by Gag-mediated recruitment of Bro1 to the plasma membrane	PubMed
p6	gag	Knockdown of Alix by shRNA reduces the association of HIV-1 p6 with galectin-3 in cells	PubMed
	gag	A novel tetra-peptide insertion (PYXE), identified in Gag-p6 ALIX-binding region in protease inhibitor failure Indian HIV-1C sequences, may be predicted to restore ALIX-mediated virus release pathway	PubMed
	gag	The S40F mutation in HIV-1 p6 enhances ALIX binding to HIV-1 Gag in the yeast two-hybrid assay. The Y36S mutation introduced into the S40F mutant disrupts ALIX interaction with Gag and restores spherical particle formation in cells	PubMed
	gag	The phenolic hydroxyl of the tyrosine residue in the 36YPXnL domain of HIV-1 p6 is essential for ALIX-mediated HIV-1 budding. Y36F mutant blocks ALIX recruitment	PubMed
	gag	Mutations (Y36A, Y36S/L44H, Y36S/L44R, L41A, and L41R) between p6 residues 36 and 44 inhibit the Alix-p6 interaction	PubMed
	gag	AIP1 is incorporated into HIV-1 virions through its interaction with HIV-1 p6	PubMed
	gag	AIP1 binds to the LXXLF motif in HIV-1 p6 (amino acids 41-44) and along with TSG101 acts as a component of the viral budding machinery	PubMed
	gag	Natural loss of L35Y36 residues in p6 of HIV-1 subtype C prevents p6 from ALIX interaction	PubMed
	gag	ALIX proteins with point mutations (Val498Asp, Phe676Asp, and Ile683Asp) that inhibit the p6 36YPLASL41 binding fail to rescue HIV-1 deltaPTAP release or infectivity	PubMed
	gag	An ALIX fragment encompassing residues 391-510 is a minimal p6deltaSQKQ binding site within the middle region of ALIX	PubMed
	gag	The Bro1 domain of Alix inhibits HIV budding by targeting both PTAP/TSG101 and LYPXnL/Alix pathways	PubMed
	gag	The ability of ALIX to rescue an HIV p6 PTAP mutant depends on its C-terminal proline-rich domain (PRD), but not on its binding sites for Tsg101	PubMed
	gag	Overexpression of the Alix 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	PubMed
	gag	Residues 360-702 of Alix spans the shape of the letter 'V' and is termed the V domain, which has a topologically complex arrangement of 11 alpha-helices; Phe676 is at the center of a large hydrophobic pocket and is crucial for binding to HIV-1 p6	PubMed

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Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

Cda1ef02 (e-PCR)
- UniSTS:56101

PDCD6IP_3260 (e-PCR)
- UniSTS:462389

A005P37 (e-PCR)
- UniSTS:27497

G32258 (e-PCR)
- UniSTS:116857

SHGC-76820 (e-PCR)
- UniSTS:42121

G43299 (e-PCR)
- UniSTS:94929

RH48396 (e-PCR)
- UniSTS:9702

RH93901 (e-PCR)
- UniSTS:86502

STS-R60314 (e-PCR)
- UniSTS:81899

D9S1961 (e-PCR)
- UniSTS:58091

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables calcium-dependent protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein homodimerization activity	IPI Inferred from Physical Interaction more info	PubMed
enables proteinase activated receptor binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
involved_in actomyosin contractile ring assembly	ISS Inferred from Sequence or Structural Similarity more info
involved_in apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in bicellular tight junction assembly	ISS Inferred from Sequence or Structural Similarity more info
involved_in extracellular exosome biogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in macroautophagy	ISS Inferred from Sequence or Structural Similarity more info
involved_in maintenance of epithelial cell apical/basal polarity	ISS Inferred from Sequence or Structural Similarity more info
involved_in midbody abscission	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in mitotic cytokinesis	IBA Inferred from Biological aspect of Ancestor more info
involved_in mitotic cytokinesis	IDA Inferred from Direct Assay more info	PubMed
NOT involved_in mitotic metaphase chromosome alignment	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in multivesicular body assembly	NAS Non-traceable Author Statement more info	PubMed
involved_in multivesicular body sorting pathway	IEA Inferred from Electronic Annotation more info
NOT involved_in nucleus organization	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of exosomal secretion	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of extracellular exosome assembly	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in protein homooligomerization	IDA Inferred from Direct Assay more info	PubMed
involved_in protein transport	IEA Inferred from Electronic Annotation more info
involved_in regulation of centrosome duplication	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of extracellular exosome assembly	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of membrane permeability	ISS Inferred from Sequence or Structural Similarity more info
NOT involved_in regulation of mitotic spindle assembly	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in viral budding	IDA Inferred from Direct Assay more info	PubMed
involved_in viral budding via host ESCRT complex	IGI Inferred from Genetic Interaction more info	PubMed
involved_in viral budding via host ESCRT complex	NAS Non-traceable Author Statement more info	PubMed

Component	Evidence Code	Pubs
located_in Flemming body	IDA Inferred from Direct Assay more info	PubMed
located_in actomyosin	ISS Inferred from Sequence or Structural Similarity more info
located_in bicellular tight junction	IEA Inferred from Electronic Annotation more info
located_in centrosome	IEA Inferred from Electronic Annotation more info
located_in cytosol	TAS Traceable Author Statement more info
located_in endoplasmic reticulum exit site	IMP Inferred from Mutant Phenotype more info	PubMed
is_active_in endosome	IBA Inferred from Biological aspect of Ancestor more info
located_in extracellular exosome	HDA more info	PubMed
located_in extracellular exosome	IDA Inferred from Direct Assay more info	PubMed
located_in extracellular vesicle	HDA more info	PubMed
located_in focal adhesion	HDA more info	PubMed
located_in immunological synapse	IDA Inferred from Direct Assay more info	PubMed
located_in melanosome	IEA Inferred from Electronic Annotation more info
located_in membrane	HDA more info	PubMed

General protein information

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Preferred Names: programmed cell death 6-interacting protein

Names: ALG-2 interacting protein 1; ALG-2-interacting protein X; PDCD6-interacting protein; apoptosis-linked gene 2-interacting protein X; dopamine receptor interacting protein 4

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_033961.1 RefSeqGene

Range

5060..76133

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001162429.3 → NP_001155901.1 programmed cell death 6-interacting protein isoform 2

Status: REVIEWED

Description

Transcript Variant: This variant (2) represents the longest transcript and encodes the longest isoform (2).

Source sequence(s)

AB037796, AL695629, BC068454, CR739098, DA149360, DA652213

Consensus CDS

CCDS54561.1

UniProtKB/TrEMBL

Q4W4Y1

Related

ENSP00000411825.2, ENST00000457054.6

Conserved Domains (4) summary

cd09235
Location:365 → 703

V_Alix; Middle V-domain of mammalian Alix and related domains are dimerization and protein interaction modules

cd09240
Location:2 → 350

BRO1_Alix; Protein-interacting, N-terminal, Bro1-like domain of mammalian Alix and related domains

smart00818
Location:819 → 873

Amelogenin; Amelogenins, cell adhesion proteins, play a role in the biomineralisation of teeth

PHA03247
Location:717 → 871

PHA03247; large tegument protein UL36; Provisional
NM_001256192.2 → NP_001243121.1 programmed cell death 6-interacting protein isoform 3

See identical proteins and their annotated locations for NP_001243121.1

Status: REVIEWED

Description

Transcript Variant: This variant (4) lacks several 3' exons but contains an alternate 3' exon, and it thus differs in the 3' coding region and 3' UTR, compared to variant 2. The encoded isoform (3) has a distinct and significantly shorter C-terminus, compared to isoform 2.

Source sequence(s)

AC112220, AI346371, DA652213, GQ131806

UniProtKB/TrEMBL

A0A3B3IT07

Conserved Domains (1) summary

cl14649
Location:2 → 239

BRO1_Alix_like; Protein-interacting Bro1-like domain of mammalian Alix and related domains
NM_013374.6 → NP_037506.2 programmed cell death 6-interacting protein isoform 1

See identical proteins and their annotated locations for NP_037506.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) uses an alternate in-frame splice site in the central coding region, compared to variant 2, resulting in an isoform (1) that is shorter than isoform 2.

Source sequence(s)

AB037796, AF349951, AL695629, BC020066, CR739098, DA149360

Consensus CDS

CCDS2660.1

UniProtKB/Swiss-Prot

C5MQH7, E9PFU1, Q6NUS1, Q8WUM4, Q9BX86, Q9NUN0, Q9P2H2, Q9UKL5

UniProtKB/TrEMBL

Q4W4Y1

Related

ENSP00000307387.3, ENST00000307296.8

Conserved Domains (4) summary

cd09235
Location:360 → 698

V_Alix; Middle V-domain of mammalian Alix and related domains are dimerization and protein interaction modules

cd09240
Location:2 → 345

BRO1_Alix; Protein-interacting, N-terminal, Bro1-like domain of mammalian Alix and related domains

cl25716
Location:814 → 868

Amelogenin; Amelogenin

cl26464
Location:712 → 866

Atrophin-1; Atrophin-1 family

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000003.12 Reference GRCh38.p14 Primary Assembly

Range

33798630..33869703

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_011533252.2 → XP_011531554.1 programmed cell death 6-interacting protein isoform X1

See identical proteins and their annotated locations for XP_011531554.1

UniProtKB/TrEMBL

B4DHD2

Conserved Domains (4) summary

cd09235
Location:175 → 513

V_Alix; Middle V-domain of mammalian Alix and related domains are dimerization and protein interaction modules

pfam13949
Location:227 → 516

ALIX_LYPXL_bnd; ALIX V-shaped domain binding to HIV

cl14649
Location:1 → 160

BRO1_Alix_like; Protein-interacting Bro1-like domain of mammalian Alix and related domains

cl23782
Location:630 → 683

RCR; Chitin synthesis regulation, resistance to Congo red
XM_047447042.1 → XP_047302998.1 programmed cell death 6-interacting protein isoform X1

Alternate T2T-CHM13v2.0

Genomic

NC_060927.1 Alternate T2T-CHM13v2.0

Range

33799362..33870437

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054344819.1 → XP_054200794.1 programmed cell death 6-interacting protein isoform X1

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

NR_027867.1: Suppressed sequence

Description

NR_027867.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript, which appears to be incompletely processed at its 5'' end.