TIPE3

Summary

TIPE3 (TNF alpha induced protein 8 like 3, HGNC:20620) is a protein-coding gene on chromosome 15q21.2, encoding Tumor necrosis factor alpha-induced protein 8-like protein 3 (Q5GJ75). Acts as a lipid transfer protein.

Predicted to enable phosphatidylinositol binding activity and phosphatidylinositol transfer activity. Predicted to be involved in 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate metabolic process; phospholipid transport; and positive regulation of ERK1 and ERK2 cascade. Located in cytosol and nucleoplasm.

Source: NCBI Gene 388121 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• MANE Select transcript: NM_001311175

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20620
Approved symbol	TIPE3
Name	TNF alpha induced protein 8 like 3
Location	15q21.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ41287
Ensembl gene	ENSG00000183578
Ensembl biotype	protein_coding
OMIM	616438
Entrez	388121

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000327536, ENST00000637513, ENST00000649177

RefSeq mRNA: 2 — MANE Select: NM_001311175 NM_001311175, NM_207381

CCDS: CCDS32241, CCDS81881

Canonical transcript exons

ENST00000637513 — 2 exons

Exon	Start	End
ENSE00003800134	51056601	51058443
ENSE00003800682	51094544	51094906

Expression profiles

Bgee: expression breadth ubiquitous, 129 present calls, max score 95.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.9612 / max 144.7281, expressed in 977 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149891	2.2564	479
149890	2.0494	765
149889	1.6554	668

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left uterine tube	UBERON:0001303	95.44	gold quality
body of uterus	UBERON:0009853	93.58	gold quality
smooth muscle tissue	UBERON:0001135	93.53	gold quality
myometrium	UBERON:0001296	92.56	gold quality
right coronary artery	UBERON:0001625	92.31	gold quality
fallopian tube	UBERON:0003889	91.67	gold quality
mucosa of stomach	UBERON:0001199	91.61	gold quality
tibial artery	UBERON:0007610	91.56	gold quality
popliteal artery	UBERON:0002250	91.55	gold quality
cerebellar vermis	UBERON:0004720	91.09	gold quality
left coronary artery	UBERON:0001626	90.87	gold quality
descending thoracic aorta	UBERON:0002345	90.73	gold quality
lower esophagus mucosa	UBERON:0035834	90.06	gold quality
thoracic aorta	UBERON:0001515	89.20	gold quality
ascending aorta	UBERON:0001496	88.96	gold quality
quadriceps femoris	UBERON:0001377	88.42	gold quality
skin of leg	UBERON:0001511	86.42	gold quality
zone of skin	UBERON:0000014	86.13	gold quality
skin of abdomen	UBERON:0001416	85.79	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.54	gold quality
lower esophagus	UBERON:0013473	84.31	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.25	gold quality
urinary bladder	UBERON:0001255	83.29	gold quality
ectocervix	UBERON:0012249	83.12	gold quality
esophagus	UBERON:0001043	83.00	gold quality
spleen	UBERON:0002106	82.80	gold quality
right ovary	UBERON:0002118	82.76	gold quality
vagina	UBERON:0000996	82.36	gold quality
upper lobe of left lung	UBERON:0008952	82.35	gold quality
amygdala	UBERON:0001876	81.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.90
E-GEOD-70580	no	5.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

55 targeting TIPE3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-1537-5P	98.70	68.33	999
HSA-MIR-2467-3P	98.65	67.18	1969

Literature-anchored findings (GeneRIF, showing 16)

• human cancers have markedly upregulated TIPE3 expression. Knocking out TIPE3 diminishes tumorigenesis, whereas enforced TIPE3 expression enhances it in vivo (PMID:25242044)
• TIPE3 protein is highly expressed in most human carcinoma cell lines. These results suggest that TIPE3 may play important roles in carcinogenesis and cell secretion. (PMID:25479791)
• Further MD simulations confirmed the dynamic stability of these lipids in the TH domain. This computational analysis thus provides insight into the binding mode of phospholipids in the TH domain of the TIPE family of proteins. (PMID:27783229)
• TIPE3 protein was upregulated in breast cancer tissues and positively correlated to invasion and metastasis of human breast cancer cells by activating AKT and NF-kappaB signaling pathways. (PMID:28388580)
• In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. (Meta-analysis) (PMID:29422769)
• High TIPE3 expression in the plasma membrane is associated with non-small-cell lung cancer. (PMID:29510688)
• TIPE3 downregulation correlates with its CpG island hypermethylation in several solid cancers. TIPE3 acts as a tumor suppressor in nasopharyngeal carcinoma (NPC), providing a further insight into NPC progression and representing a potential prognostic biomarker for NPC (PMID:30217224)
• TIPE3 inhibits p38 phosphorylation and blocks p38 nuclear translocation to inhibit glioblastoma cell apoptosis. (PMID:30639532)
• TNFAIP8L3 is highly expressed in human cancer cells and promotes carcinogenesis. Silence of TNFAIP8L3 diminished Gastric Cancer cells migration mediated by miR-9-5p. (PMID:31140050)
• Effects of the long and short isoforms of TIPE3 on the growth and metastasis of gastric cancer. (PMID:31978770)
• Loss of TIPE3 reduced the proliferation, survival and migration of lung cancer cells through inactivation of Akt/mTOR, NF-kappaB, and STAT-3 signaling cascades. (PMID:35041835)
• Tumor necrosis factor-alpha-inducible protein 8-like protein 3 (TIPE3): a novel prognostic factor in colorectal cancer. (PMID:36755222)
• TIPE3 protects mice from lipopolysaccharide-induced acute lung injury. (PMID:36842565)
• TIPE3 represses head and neck squamous cell carcinoma progression via triggering PGAM5 mediated mitochondria dysfunction. (PMID:37024453)
• Comprehensive analysis of the prognostic and immunological roles of TIPE3 in Colon Cancer. (PMID:38071098)
• Down-regulated expression of TIPE3 inhibits malignant progression of non-small cell lung cancer via Wnt signaling. (PMID:38759744)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnfaip8l3	ENSDARG00000088709
mus_musculus	Tnfaip8l3	ENSMUSG00000074345
rattus_norvegicus	Tnfaip8l3	ENSRNOG00000024230
drosophila_melanogaster	sigmar	FBGN0034894

Paralogs (3): TNFAIP8 (ENSG00000145779), TNFAIP8L2 (ENSG00000163154), TNFAIP8L1 (ENSG00000185361)

Protein

Protein identifiers

Tumor necrosis factor alpha-induced protein 8-like protein 3 — Q5GJ75 (reviewed: Q5GJ75)

All UniProt accessions (3): A0A1B0GTK8, A0A494C051, Q5GJ75

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a lipid transfer protein. Preferentially captures and shuttles two lipid second messengers, i.e., phosphatidylinositol 4,5- bisphosphate and phosphatidylinositol 3,4,5-trisphosphate and increases their levels in the plasma membrane. Additionally, may also function as a lipid-presenting protein to enhance the activity of the PI3K-AKT and MEK-ERK pathways. May act as a regulator of tumorigenesis through its activation of phospholipid signaling.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Widely expressed (at protein level). Highly expressed in most carcinoma cell lines.

Similarity. Belongs to the TNFAIP8 family.

RefSeq proteins (2): NP_001298104, NP_997264 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008477	TNFAIP8-like	Family
IPR038355	TNFAIP8_sf	Homologous_superfamily

Pfam: PF05527

UniProt features (13 total): helix 9, region of interest 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4Q9V	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5GJ75-F1	74.88	0.51

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1483255	PI Metabolism

MSigDB gene sets: 76 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_PHOSPHOLIPID_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_MEMBRANE_ORGANIZATION, GOBP_LIPID_LOCALIZATION, AP2_Q6_01, GOBP_ERK1_AND_ERK2_CASCADE

GO Biological Process (7): phospholipid metabolic process (GO:0006644), phospholipid transport (GO:0015914), regulation of apoptotic process (GO:0042981), positive regulation of ERK1 and ERK2 cascade (GO:0070374), 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate metabolic process (GO:1902633), lipid transport (GO:0006869), intermembrane lipid transfer (GO:0120009)

GO Molecular Function (3): phosphatidylinositol transfer activity (GO:0008526), phosphatidylinositol binding (GO:0035091), protein binding (GO:0005515)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Phospholipid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
lipid transport	2
lipid metabolic process	1
organophosphate metabolic process	1
organophosphate ester transport	1
apoptotic process	1
regulation of programmed cell death	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
glycerophospholipid metabolic process	1
transport	1
lipid localization	1
membrane organization	1
phosphatidylinositol binding	1
lipid transfer activity	1
anion binding	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

264 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIPE3	GLDN	Q6ZMI3	540
TIPE3	FBXW5	Q969U6	447
TIPE3	LYSMD2	Q8IV50	445
TIPE3	IL17REL	Q6ZVW7	396
TIPE3	VSTM2B	A6NLU5	356
TIPE3	COG6	Q9Y2V7	338
TIPE3	OR1J2	Q8NGS2	321
TIPE3	PLAC9	Q5JTB6	317
TIPE3	CTDNEP1	O95476	306
TIPE3	TNFAIP2	Q03169	306
TIPE3	FAM174B	Q3ZCQ3	299
TIPE3	ADGRL2	O95490	293
TIPE3	SLC35F2	Q8IXU6	293
TIPE3	IL20RA	Q9UHF4	284
TIPE3	IL1RAPL2	Q9NP60	272

IntAct

7 interactions, top by confidence:

A	B	Type	Score
SDCBP	TNFAIP8L3	psi-mi:“MI:0915”(physical association)	0.560
TNFAIP8L3	CBY1	psi-mi:“MI:0915”(physical association)	0.560
SDCBP	TNFAIP8L3	psi-mi:“MI:0915”(physical association)	0.000
TNFAIP8L3	CBY1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): TNFAIP8L3 (Two-hybrid), TNFAIP8L3 (Two-hybrid), TNFAIP8L3 (Affinity Capture-MS), UFL1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0JMD2, A2AKX3, A5WUT8, A5WWB6, A6H754, A6H7E2, A9CB91, E1BLZ4, O08648, P03247, P11824, Q1RMQ5, Q28HY7, Q2HRD2, Q32KP7, Q3URK1, Q3ZAV0, Q499E6, Q5GJ75, Q5RA87, Q5U4U4, Q5XIC3, Q5ZM13, Q60664, Q68DK2, Q6P1U0, Q6P9N1, Q6ZPK7, Q7L3B6, Q7SYV9, Q80TA9, Q86WR6, Q8C4J0, Q8IWA6, Q8R060, Q96GY3, Q99L00, Q9BT25, Q9BYI3, Q9CQS9

Diamond homologs: A4IF78, A5PK29, A9X192, B0KWC3, B2KI57, B4UT01, B5X737, B7NZC7, O95379, Q1ECV8, Q28I19, Q28ZG0, Q3TBL6, Q3ZBK5, Q5BKH4, Q5GJ75, Q5RF18, Q5ZI78, Q5ZJU8, Q6AYJ8, Q6DFE2, Q6GQ44, Q6P589, Q6P7I6, Q7KVH9, Q7SZE8, Q7T364, Q7T3D0, Q8K288, Q8WVP5, Q921Z5, Q9D8Y7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

986 predictions. Top by Δscore:

Variant	Effect	Δscore
15:51058444:C:CC	acceptor_gain	1.0000
15:51058440:GGAC:G	acceptor_gain	0.9900
15:51058441:GACC:G	acceptor_loss	0.9900
15:51058449:G:GC	acceptor_gain	0.9900
15:51059565:T:C	donor_gain	0.9900
15:51058441:GAC:G	acceptor_gain	0.9800
15:51058449:G:C	acceptor_gain	0.9800
15:51082784:A:AC	donor_gain	0.9800
15:51082785:C:CC	donor_gain	0.9800
15:51104972:T:TA	donor_gain	0.9800
15:51070267:C:CC	acceptor_gain	0.9700
15:51058439:AGGAC:A	acceptor_gain	0.9600
15:51058441:GACCT:G	acceptor_gain	0.9600
15:51058442:ACC:A	acceptor_gain	0.9600
15:51058443:CCTAT:C	acceptor_gain	0.9600
15:51058444:C:A	acceptor_gain	0.9600
15:51058445:T:C	acceptor_gain	0.9600
15:51094540:GTAC:G	donor_loss	0.9600
15:51094541:TAC:T	donor_loss	0.9600
15:51094542:ACCT:A	donor_loss	0.9600
15:51094543:CCT:C	donor_loss	0.9600
15:51105068:C:A	donor_gain	0.9600
15:51058440:GGACC:G	acceptor_gain	0.9500
15:51058442:AC:A	acceptor_gain	0.9500
15:51058443:CC:C	acceptor_gain	0.9500
15:51058446:A:C	acceptor_gain	0.9500
15:51094539:GGTAC:G	donor_loss	0.9500
15:51070265:CA:C	acceptor_gain	0.9400
15:51104973:C:A	donor_gain	0.9400
15:51070263:CTCA:C	acceptor_gain	0.9000

AlphaMissense

1378 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:51058038:A:G	L241P	0.998
15:51058109:G:C	F217L	0.998
15:51058109:G:T	F217L	0.998
15:51058111:A:G	F217L	0.998
15:51058130:G:C	F210L	0.998
15:51058130:G:T	F210L	0.998
15:51058132:A:G	F210L	0.998
15:51058133:G:C	S209R	0.998
15:51058133:G:T	S209R	0.998
15:51058135:T:G	S209R	0.998
15:51058206:A:G	F185S	0.998
15:51058235:T:A	K175N	0.998
15:51058235:T:G	K175N	0.998
15:51058236:T:A	K175I	0.998
15:51058237:T:C	K175E	0.998
15:51058247:C:A	K171N	0.998
15:51058247:C:G	K171N	0.998
15:51058249:T:C	K171E	0.998
15:51058337:G:C	S141R	0.998
15:51058337:G:T	S141R	0.998
15:51058339:T:G	S141R	0.998
15:51058017:C:G	R248P	0.997
15:51058149:G:T	A204D	0.997
15:51058150:C:G	A204P	0.997
15:51058260:T:A	K167I	0.997
15:51058317:A:G	L148P	0.997
15:51058018:G:T	R248S	0.996
15:51058161:A:G	L200P	0.996
15:51058404:G:T	A119D	0.996
15:51058005:A:T	V252D	0.995

dbSNP variants (sampled 300 via entrez): RS1000048803 (15:51064769 C>T), RS1000056101 (15:51098164 A>C,G), RS1000064894 (15:51078698 C>T), RS1000126011 (15:51086090 T>C), RS1000137542 (15:51069876 C>G,T), RS1000154969 (15:51090597 T>C), RS1000209307 (15:51106630 T>C), RS1000331832 (15:51065099 C>T), RS1000378242 (15:51070285 C>T), RS1000400721 (15:51078954 G>C), RS1000420502 (15:51093811 T>C), RS1000595788 (15:51076101 A>G,T), RS1000609773 (15:51085859 T>C), RS1000650908 (15:51077747 T>A,G), RS1000666091 (15:51060805 T>G)

Disease associations

OMIM: gene MIM:616438 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000579_9	Cognitive performance	9.000000e-06
GCST002794_10	Airway wall thickness	3.000000e-06
GCST002794_18	Airway wall thickness	2.000000e-06
GCST002794_4	Airway wall thickness	8.000000e-06
GCST003485_13	Response to fenofibrate (HDL cholesterol levels)	5.000000e-07
GCST003485_14	Response to fenofibrate (HDL cholesterol levels)	5.000000e-07
GCST008839_358	Height	8.000000e-19
GCST90000025_213	Appendicular lean mass	5.000000e-18
GCST90011899_122	Aspartate aminotransferase levels	2.000000e-13
GCST90013442_23	Keratoconus	8.000000e-10
GCST90020028_1739	Hip circumference adjusted for BMI	2.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0006898	airway wall thickness measurement
EFO:0007805	HDL cholesterol change measurement
EFO:0004980	appendicular lean mass
EFO:0004736	aspartate aminotransferase measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases expression	3
Air Pollutants	decreases expression, increases abundance	2
Tobacco Smoke Pollution	decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
bisphenol A	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, increases reaction	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
jinfukang	increases expression	1
Temozolomide	decreases expression	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Arsenic	increases abundance, decreases expression	1
Biological Factors	decreases expression	1
Calcitriol	increases expression	1
Doxorubicin	decreases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Lipopolysaccharides	decreases expression, affects cotreatment, increases reaction	1
Malathion	decreases expression	1
Methapyrilene	decreases methylation	1
Pentachlorophenol	increases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1

Clinical trials (associated diseases)

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