TMEM129

Summary

TMEM129 (transmembrane protein 129, E3 ubiquitin ligase, HGNC:25137) is a protein-coding gene on chromosome 4p16.3, encoding E3 ubiquitin-protein ligase TM129 (A0AVI4). E3 ubiquitin-protein ligase involved in ER-associated protein degradation, preferentially associates with the E2 enzyme UBE2J2.

Enables ubiquitin protein ligase activity. Involved in protein polyubiquitination; retrograde protein transport, ER to cytosol; and ubiquitin-dependent protein catabolic process. Located in endoplasmic reticulum.

Source: NCBI Gene 92305 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 78 total — 1 pathogenic
• MANE Select transcript: NM_001127266

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25137
Approved symbol	TMEM129
Name	transmembrane protein 129, E3 ubiquitin ligase
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	D4S2561E
Ensembl gene	ENSG00000168936
Ensembl biotype	protein_coding
OMIM	615975
Entrez	92305

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000303277, ENST00000382936, ENST00000460722, ENST00000476253, ENST00000480360, ENST00000874437, ENST00000874438, ENST00000954371

RefSeq mRNA: 2 — MANE Select: NM_001127266 NM_001127266, NM_138385

CCDS: CCDS3351, CCDS46998

Canonical transcript exons

ENST00000382936 — 4 exons

Exon	Start	End
ENSE00001165401	1718152	1718626
ENSE00001506961	1717516	1717675
ENSE00001609898	1715952	1717428
ENSE00001830879	1720633	1721323

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 95.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.7841 / max 62.5457, expressed in 1775 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51089	8.4186	1715
51090	3.2302	1410
51087	1.0818	691
51088	1.0536	566

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	95.91	gold quality
kidney epithelium	UBERON:0004819	95.53	gold quality
apex of heart	UBERON:0002098	95.51	gold quality
endothelial cell	CL:0000115	95.32	gold quality
adenohypophysis	UBERON:0002196	95.27	gold quality
oocyte	CL:0000023	94.86	gold quality
pituitary gland	UBERON:0000007	94.22	gold quality
pancreatic ductal cell	CL:0002079	94.21	silver quality
medial globus pallidus	UBERON:0002477	94.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.19	gold quality
right lobe of thyroid gland	UBERON:0001119	94.16	gold quality
metanephros cortex	UBERON:0010533	94.06	gold quality
left ventricle myocardium	UBERON:0006566	94.04	gold quality
renal medulla	UBERON:0000362	94.01	gold quality
left lobe of thyroid gland	UBERON:0001120	93.69	gold quality
cerebellar hemisphere	UBERON:0002245	93.59	gold quality
cardiac muscle of right atrium	UBERON:0003379	93.58	gold quality
cerebellar cortex	UBERON:0002129	93.47	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.40	gold quality
lower esophagus	UBERON:0013473	93.38	gold quality
transverse colon	UBERON:0001157	93.30	gold quality
mucosa of transverse colon	UBERON:0004991	93.30	gold quality
right atrium auricular region	UBERON:0006631	93.17	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.15	gold quality
cardiac atrium	UBERON:0002081	93.13	gold quality
body of pancreas	UBERON:0001150	92.98	gold quality
parotid gland	UBERON:0001831	92.97	gold quality
putamen	UBERON:0001874	92.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.87	gold quality
body of stomach	UBERON:0001161	92.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

52 targeting TMEM129, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-6852-5P	99.17	66.69	2073

Literature-anchored findings (GeneRIF, showing 5)

• TMEM129 is an integral part of the Endoplasmic Reticulum-resident dislocation complex mediating US11-induced HLA class I degradation. (PMID:24807418)
• TMEM129 contains an unusual cysteine-only RING with intrinsic E3 ligase activity and is recruited to US11 via Derlin-1. (PMID:25030448)
• TRC8 and TMEM129 are endoplasmic reticulum-associated degradation ubiquitin E3 ligases for viral and cellular targeting of MHC class I. (Review) (PMID:26210183)
• This insertion in the endoplasmic reticulum membrane positions the C-terminal really interesting new gene (RING) domain of TMEM129 in the cytosol, making it available to catalyze ubiquitination reactions that are required for cytosolic degradation of secretory proteins. (PMID:27854284)
• Identification of TMEM129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk. (PMID:35941660)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem129	ENSDARG00000075346
mus_musculus	Tmem129	ENSMUSG00000019295
rattus_norvegicus	Tmem129	ENSRNOG00000017329
drosophila_melanogaster	CG14646	FBGN0037241
caenorhabditis_elegans		WBGENE00007941

Protein

Protein identifiers

E3 ubiquitin-protein ligase TM129 — A0AVI4 (reviewed: A0AVI4)

Alternative names: RING-type E3 ubiquitin transferase TM129

All UniProt accessions (3): A0AVI4, H7C4G7, H7C4I8

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase involved in ER-associated protein degradation, preferentially associates with the E2 enzyme UBE2J2. Exploited by viral US11 proteins to mediate HLA class I proteins degradation.

Subunit / interactions. Integral component of ER-resident dislocation complexes.

Subcellular location. Endoplasmic reticulum membrane.

Domain organisation. The RING-type zinc finger domain is responsible for E3 ubiquitin ligase activity.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the TMEM129 family.

Isoforms (2)

UniProt ID	Names	Canonical?
A0AVI4-1	1	yes
A0AVI4-2	2

RefSeq proteins (2): NP_001120738, NP_612394 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018801	TM129	Family

Pfam: PF10272

UniProt features (12 total): topological domain 4, transmembrane region 3, splice variant 2, chain 1, sequence variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A0AVI4-F1	88.77	0.63

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins

MSigDB gene sets: 109 (showing top): GOBP_ENDOPLASMIC_RETICULUM_TO_CYTOSOL_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CHANDRAN_METASTASIS_DN, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, chr4p16, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, GGTGAAG_MIR412, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_ERAD_PATHWAY, TGCCTTA_MIR124A, GOBP_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (6): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), response to unfolded protein (GO:0006986), protein ubiquitination (GO:0016567), retrograde protein transport, ER to cytosol (GO:0030970), ERAD pathway (GO:0036503)

GO Molecular Function (5): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein ubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	2
modification-dependent protein catabolic process	1
response to topologically incorrect protein	1
protein modification by small protein conjugation	1
protein exit from endoplasmic reticulum	1
ERAD pathway	1
endoplasmic reticulum to cytosol transport	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

839 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM129	RNF139	Q8WU17	721
TMEM129	TACC3	Q9Y6A5	677
TMEM129	UBE2J2	Q8N2K1	675
TMEM129	FAM53A	Q6NSI3	654
TMEM129	RNF185	Q96GF1	590
TMEM129	RNF170	Q96K19	587
TMEM129	RNF5	Q99942	579
TMEM129	SEL1L	Q9UBV2	573
TMEM129	MARCHF6	O60337	563
TMEM129	AMFR	P26442	521
TMEM129	RNF223	E7ERA6	505
TMEM129	SLBP	Q14493	500
TMEM129	ENKD1	Q9H0I2	483
TMEM129	USH2A	O75445	475
TMEM129	RNFT1	Q5M7Z0	472

IntAct

7 interactions, top by confidence:

A	B	Type	Score
MSANTD3	TMEM129	psi-mi:“MI:0915”(physical association)	0.370
DLC1	TMEM129	psi-mi:“MI:0915”(physical association)	0.370
TMEM129	PDGFRL	psi-mi:“MI:0915”(physical association)	0.370
KCNA2	TMEM129	psi-mi:“MI:0914”(association)	0.350
TMEM129	INHA	psi-mi:“MI:0914”(association)	0.350
SLC6A19	TMEM129	psi-mi:“MI:0914”(association)	0.350

BioGRID (42): PSMD4 (Biochemical Activity), UBE2D3 (Reconstituted Complex), UBE2J2 (Affinity Capture-Western), DERL1 (Affinity Capture-Western), DERL2 (Affinity Capture-Western), VIMP (Affinity Capture-Western), VCP (Affinity Capture-Western), SEL1L (Affinity Capture-Western), SYVN1 (Affinity Capture-Western), HLA-A (Affinity Capture-Western), TMEM129 (Biochemical Activity), UBE2D1 (Reconstituted Complex), TMEM129 (Affinity Capture-Western), DERL1 (Affinity Capture-Western), HLA-A (Affinity Capture-Western)

ESM2 similar proteins: A0A5F8AH41, A0AVI4, A0JMH2, A1Y9I9, A5WVX1, B0X4N1, B4P925, D3ZX08, O55171, O88512, O95050, O97972, P0DPD7, P0DPE0, P0DPE1, P10937, P10938, P11086, P40935, P40936, Q06AU9, Q08DK0, Q14CH7, Q32PE2, Q32Q92, Q3SZG9, Q3URQ7, Q568P9, Q5E9L5, Q5JTZ9, Q5RCH4, Q5RFR7, Q6NTR1, Q6NZB1, Q7QIL2, Q7TMC8, Q80YU0, Q8HY87, Q8K304, Q8NFF5

Diamond homologs: A0AVI4, Q08DK0, Q0IJ33, Q5ZI25, Q6IR55, Q6PD82, Q8K304

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	TMEM129	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	63
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3770227	GRCh37/hg19 4p16.3-16.2(chr4:80000-5520000)x1	Pathogenic

SpliceAI

829 predictions. Top by Δscore:

Variant	Effect	Δscore
4:1717429:CTG:C	acceptor_loss	1.0000
4:1718146:TCTTA:T	donor_loss	1.0000
4:1718147:CTTA:C	donor_loss	1.0000
4:1718148:TTAC:T	donor_loss	1.0000
4:1718149:TAC:T	donor_loss	1.0000
4:1718150:A:AC	donor_gain	1.0000
4:1718150:A:AT	donor_loss	1.0000
4:1718151:C:CC	donor_gain	1.0000
4:1718625:GCCTG:G	acceptor_loss	1.0000
4:1718626:CCT:C	acceptor_loss	1.0000
4:1718627:C:CC	acceptor_gain	1.0000
4:1717426:CTC:C	acceptor_gain	0.9900
4:1717429:C:CC	acceptor_gain	0.9900
4:1717430:T:G	acceptor_loss	0.9900
4:1717512:CCACC:C	donor_loss	0.9900
4:1717513:CA:C	donor_loss	0.9900
4:1717514:A:AC	donor_loss	0.9900
4:1717515:C:CA	donor_loss	0.9900
4:1717676:C:CC	acceptor_gain	0.9900
4:1718151:CCAG:C	donor_gain	0.9900
4:1718151:CCAGA:C	donor_gain	0.9900
4:1718622:GTAGC:G	acceptor_gain	0.9900
4:1718623:TAGC:T	acceptor_gain	0.9900
4:1718624:AGC:A	acceptor_gain	0.9900
4:1718625:GC:G	acceptor_gain	0.9900
4:1718626:CC:C	acceptor_gain	0.9900
4:1721222:AGG:A	donor_gain	0.9900
4:1717515:CCTGG:C	donor_gain	0.9800
4:1717672:CAGC:C	acceptor_gain	0.9800
4:1717677:TG:T	acceptor_loss	0.9800

AlphaMissense

2329 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:1717210:G:C	F353L	0.993
4:1717210:G:T	F353L	0.993
4:1717212:A:G	F353L	0.993
4:1717288:G:C	F327L	0.991
4:1717288:G:T	F327L	0.991
4:1717290:A:G	F327L	0.991
4:1717317:A:G	W318R	0.991
4:1717317:A:T	W318R	0.991
4:1717315:C:A	W318C	0.988
4:1717315:C:G	W318C	0.988
4:1717211:A:G	F353S	0.986
4:1717233:A:G	C346R	0.986
4:1717289:A:G	F327S	0.982
4:1717293:A:G	W326R	0.982
4:1717293:A:T	W326R	0.982
4:1717289:A:C	F327C	0.981
4:1717564:A:C	F264L	0.980
4:1717564:A:T	F264L	0.980
4:1717566:A:G	F264L	0.980
4:1717314:A:G	C319R	0.978
4:1718324:A:G	W170R	0.978
4:1718324:A:T	W170R	0.978
4:1718385:G:C	F149L	0.978
4:1718385:G:T	F149L	0.978
4:1718387:A:G	F149L	0.978
4:1720694:G:C	F48L	0.977
4:1720694:G:T	F48L	0.977
4:1720696:A:G	F48L	0.977
4:1717298:C:T	G324D	0.976
4:1718160:A:C	F224L	0.976

dbSNP variants (sampled 300 via entrez): RS1000045448 (4:1715655 C>T), RS1000204800 (4:1718582 G>A), RS1000616773 (4:1721296 C>G,T), RS1000747859 (4:1717051 G>A,C,T), RS1000790565 (4:1722759 C>T), RS1000807937 (4:1721623 C>T), RS1000826672 (4:1719428 G>A), RS1001818523 (4:1722181 C>T), RS1002422253 (4:1715886 C>G), RS1002541566 (4:1721628 A>G), RS1002650034 (4:1716932 G>A,C), RS1002885241 (4:1720559 C>T), RS1002917430 (4:1722623 G>A), RS10030268 (4:1721132 G>A,T), RS1003066759 (4:1718388 C>G,T)

Disease associations

OMIM: gene MIM:615975 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000639_2	Urinary bladder cancer	1.000000e-11
GCST000842_6	Bladder cancer	4.000000e-13
GCST002240_3	Bladder cancer	7.000000e-25
GCST010699_17	Brain morphology (min-P)	5.000000e-10
GCST010701_28	Cortical surface area (MOSTest)	3.000000e-32
GCST010702_46	Subcortical volume (MOSTest)	5.000000e-10
GCST010703_270	Brain morphology (MOSTest)	5.000000e-13
GCST011122_49	Walking pace	2.000000e-08
GCST90000529_4	Type 1 diabetes	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression	3
methylmercuric chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
monomethylarsonous acid	decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Curcumin	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Gallic Acid	increases expression	1
Hydrogen Peroxide	affects expression	1
Phenobarbital	affects expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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