IGSF8 (immunoglobulin superfamily, member 8)

2010-08-01 Yanhui H Zhang , Mekel M Richardson , Xin A Zhang Affiliation

Vascular Biology, Cancer Centers, Departments of Medicine, Molecular Science, University of Tennessee Health Science Center, Memphis, USA

Identity

HGNC

IGSF8

LOCATION

1q23.2

IMAGE

LOCUSID

93185

ALIAS

CD316,CD81P3,EWI-2,EWI2,KCT-4,LIR-D1,PGRL

FUSION GENES

Show Gene Fusions

DNA/RNA

CD316/IGSF8 gene typically contains 7 exons. The green bars represent the non-coding exons while the blue bars represent the coding ones. The length of each intron is indicated above and the size of each exon is indicated below (information sourced from Ensembl (ENSG00000162729)).

Description

Gene type: protein coding.
Gene size: 7604 bp, 7 exons.

Transcription

mRNA 2366 bp (length may vary for alternative splicing forms).
There are 5 transcripts (Ensembl).

Name	Transcript ID	Length (bp)	Protein ID	Length (aa)	Exon
IGSF8-001	ENST00000314485	2343	ENSP00000316664	613	7
IGSF8-002	ENST00000448417	1059	ENSP00000397464	301	4
IGSF8-003	ENST00000368086	2366	ENSP00000357065	613	7
IGSF8-201	ENST00000358475	2004	ENSP00000351261	526	8
IGSF8-004	ENST00000460351	876	No protein product	-	2

There are 7 putative alternative splicing forms (AceView).

IGSF8 alternative variant	mRNA size (bp)	Exons	NCBI 36, March 2006 genome (kb)	Aa	Protein size (kDa)	pI
aApr07	2352	7	7.36	674	71.8	8.2
bApr07	2304	8	7.60	664	70.4	8.3
cApr07	1995	4	2.92	311	32.7	8.2
dApr07	1005	4	5.58	283	30.5	6.7
eApr07-unspliced	6184	1	6.18	166	18.1	6.7
fApr07 (partial mRNA)	571	4	4.71	165	17.9	7.3
variant gApr07-unspliced (partial mRNA)	581	1	0.58 Appear non coding	91 Appear non coding	9.6 Appear non coding	11.5 Appear non coding

Pseudogene

IGSF8-004, an alternative splicing form of IGSF8/CD316, is predicted to have no protein product (Ensembl).

Proteins

Type I transmembrane protein CD316 contains an ectodomain that consists largely of four immunoglobulin domains, a transmembrane region, and a positively charged, 10-amino acid residue cytoplasmic tail. Glycosylation sites are found in the ectodomain and palmitoylation sites in the cytoplasmic domain. CD316 is constitutively palmitoylated and linked to actin cytoskeleton through direct association of its cytoplasmic domain with ezrin-radixin-moesin proteins. CD316 associates with tetraspanins such as CD9, CD81, and CD82.

Description

613 amino acids, molecular weight is 65034 Da.
Basal isoelectric point: 8.23 (

Expression

CD316 mRNA is ubiquitously expressed in human tissues, with high expression in brain, kidney, testis, liver and placenta, with low expression in peripheral blood cells, lung, and skeletal muscle.
CD316 protein is highly expressed in human brain (cortex, white matter, hippocampus and cerebellum), astrocytes, hepatocytes and lymphoid cells (majority of B-cells, T-cells and natural killer cells, but not on monocytes, polynuclear cells and platelets). CD316 is constitutively expressed on plasmacytoid dendritic cells and on cord blood-derived Langerhans-like cells. Upon stimulation, CD316 is expressed on monocytes, monocytes derived dendritic cells and myeloid dendritic cells.

Localisation

Plasma membrane, cell-cell contacts, microvilli.

Function

1. Suppresses cell movement and cell aggregation.
2. Regulates integrin alpha3beta1- and alpha4beta1-dependent cell morphology and cell spreading.
3. May participate in the regulation of neurite outgrowth and maintenance of the neural network in the adult brain.
4. Interacts with its ligand, HSPA8, and may influence the behavior of dendritic cells and control adaptive immune response.
5. Links tetraspanin web to the actin cytoskeleton through direct associations with ezrin-radixin-moesin proteins.
6. Inhibits glioblastoma growth in vitro and in vivo.
7. EWI-2 wint inhibits hepatitis C virus entry.
8. May play a role in fertilization. Lack of CD316 present at the cell surface of CD9-null oocytes may contribute to the loss of ability of CD9-null oocytes to fuse with sperms.

CD316 typically inhibits cell migration and negatively regulates cell proliferation. It associates with tetraspanins CD9, CD81, and CD82 and likely contributes to various functions of these associated tetraspanins. It also regulates the functions of alpha3beta1 and alpha4beta1 integrins, probably through its associated tetraspanins (Clark et al., 2001; Stipp et al., 2001; Stipp et al., 2003; Zhang et al., 2003; Kolesnikova et al., 2004; Kolesnikova et al., 2009; Sala-Valdés et al., 2006).

Homology

CD316 protein is conserved in chimpanzee, cow, mouse, rat, and zebrafish and belongs to the EWI subfamily of Ig superfamily. Other human EWI subfamily proteins include FPRP/CD9P-1, IGSF3, and CD101.

Mutations

Note

Currently there is no known disease-related or biologically significant mutation (see HGMD).

Implicated in

Entity name

Glioma or glioblastoma

Note

CD316 inhibits glioblastoma growth in vitro and in vivo. Loss of CD316 expression correlates with a shorter survival time in human glioma patients (Kolesnikova et al., 2009).

Entity name

Hepatitis and liver cancer

Note

Hepatitis C virus (HCV)-infected population has higher risk of developing liver cancer. Ectopic expression of EWI-2wint, i.e., EWI-2 without its N-terminus, can inhibit HCV entry and reduce HCV infection (Rocha-Perugini et al., 2008).

Entity name

Autoimmune diseases

Note

It was reported that CD316 is an inducible receptor of HSPA8 on human dendritic cells, it may control the adaptive immune response through its influence on the behavior of dendritic cells. Therefore it maybe utilized in the treatment of antoimmune diseases such as rheumatoid arthritis (Kettner et al., 2007).

Entity name

Infertility

Note

CD316 plays a role in fertilization. Oocytes from CD9 null mice cannot fuse with sperm. The level of CD316 proteins on the CD9-null oocyte surface is less than 10% of that on the wild-type one. The loss of CD316 on the CD9-null oocyte surface may be responsible for the loss of fusion ability (He et al., 2009; Glazar et al., 2009).

Entity name

Type 2 diabetes mellitus

Note

CD316 is a candidate for human disorders on 1q22-q23, including type 2 diabetes mellitus (Murdoch et al., 2003).

Article Bibliography

Pubmed ID	Last Year	Title	Authors
12708969	2003	EWI-2 is a new component of the tetraspanin web in hepatocytes and lymphoid cells.	Charrin S et al
19762465	2009	The Ig domain protein CD9P-1 down-regulates CD81 ability to support Plasmodium yoelii infection.	Charrin S et al
11673522	2001	PGRL is a major CD81-associated protein on lymphocytes and distinguishes a new family of cell surface proteins.	Clark KL et al
19328198	2009	Mutation of juxtamembrane cysteines in the tetraspanin CD81 affects palmitoylation and alters interaction with other proteins at the cell surface.	Delandre C et al
19210920	2009	Immunoglobulin superfamily member IgSF8 (EWI-2) and CD9 in fertilisation: evidence of distinct functions for CD9 and a CD9-associated protein in mammalian sperm-egg interaction.	Glazar AI et al
19107828	2009	Loss of surface EWI-2 on CD9 null oocytes.	He ZY et al
17785435	2007	EWI-2/CD316 is an inducible receptor of HSPA8 on human dendritic cells.	Kettner S et al
19107234	2009	Glioblastoma inhibition by cell surface immunoglobulin protein EWI-2, in vitro and in vivo.	Kolesnikova TV et al
15004227	2004	Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Galpha q/11 association.	Little KD et al
12595239	2003	Genomic organization and embryonic expression of Igsf8, an immunoglobulin superfamily member implicated in development of the nervous system and organ epithelia.	Murdoch JN et al
18382656	2008	The CD81 partner EWI-2wint inhibits hepatitis C virus entry.	Rocha-Perugini V et al
16690612	2006	EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin-radixin-moesin proteins.	Sala-Valdés M et al
14662754	2003	EWI-2 regulates alpha3beta1 integrin-dependent cell functions on laminin-5.	Stipp CS et al
16203089	2006	Neuronal expression of keratinocyte-associated transmembrane protein-4, KCT-4, in mouse brain and its up-regulation by neurite outgrowth of Neuro-2a cells.	Yamada O et al
16537545	2006	Contrasting effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization.	Yang XH et al
12750295	2003	EWI2/PGRL associates with the metastasis suppressor KAI1/CD82 and inhibits the migration of prostate cancer cells.	Zhang XA et al

Other Information

Locus ID:

NCBI: 93185
MIM: 606644
HGNC: 17813
Ensembl: ENSG00000162729

Variants:

dbSNP: 93185
ClinVar: 93185
TCGA: ENSG00000162729
COSMIC: IGSF8

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000162729	ENST00000314485	Q969P0
ENSG00000162729	ENST00000368086	Q969P0
ENSG00000162729	ENST00000448417	C9J8Z4
ENSG00000162729	ENST00000614243	Q969P0

Expression (GTEx)

100

150

200

250

300

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38657602	2024	IGSF8 is an innate immune checkpoint and cancer immunotherapy target.	2
38657602	2024	IGSF8 is an innate immune checkpoint and cancer immunotherapy target.	2
36788350	2023	EWI2 and its relatives in Tetraspanin-enriched membrane domains regulate malignancy.	2
36788350	2023	EWI2 and its relatives in Tetraspanin-enriched membrane domains regulate malignancy.	2
35339615	2022	EWI2 promotes endolysosome-mediated turnover of growth factor receptors and integrins to suppress lung cancer.	2
35773608	2022	EWI2 prevents EGFR from clustering and endocytosis to reduce tumor cell movement and proliferation.	0
35339615	2022	EWI2 promotes endolysosome-mediated turnover of growth factor receptors and integrins to suppress lung cancer.	2
35773608	2022	EWI2 prevents EGFR from clustering and endocytosis to reduce tumor cell movement and proliferation.	0
33605506	2021	EWI-2 controls nucleocytoplasmic shuttling of EGFR signaling molecules and miRNA sorting in exosomes to inhibit prostate cancer cell metastasis.	11
33605506	2021	EWI-2 controls nucleocytoplasmic shuttling of EGFR signaling molecules and miRNA sorting in exosomes to inhibit prostate cancer cell metastasis.	11
31757023	2019	EWI-2 Inhibits Cell-Cell Fusion at the HIV-1 Virological Presynapse.	7
31757023	2019	EWI-2 Inhibits Cell-Cell Fusion at the HIV-1 Virological Presynapse.	7
25656846	2015	EWI-2 negatively regulates TGF-β signaling leading to altered melanoma growth and metastasis.	28
25656846	2015	EWI-2 negatively regulates TGF-β signaling leading to altered melanoma growth and metastasis.	28
23351194	2013	EWI-2wint promotes CD81 clustering that abrogates Hepatitis C Virus entry.	22

Citation

Yanhui H Zhang ; Mekel M Richardson ; Xin A Zhang

IGSF8 (immunoglobulin superfamily, member 8)

Atlas Genet Cytogenet Oncol Haematol. 2010-08-01

Online version: http://atlasgeneticsoncology.org/gene/45820/igsf8-(immunoglobulin-superfamily-member-8)