ERO1A

Summary

ERO1A (endoplasmic reticulum oxidoreductase 1 alpha, HGNC:13280) is a protein-coding gene on chromosome 14q22.1, encoding ERO1-like protein alpha (Q96HE7). Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum.

Enables oxidoreductase activity. Involved in cell redox homeostasis and chaperone cofactor-dependent protein refolding. Located in Golgi lumen; endoplasmic reticulum; and extracellular space.

Source: NCBI Gene 30001 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 67 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_014584

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13280
Approved symbol	ERO1A
Name	endoplasmic reticulum oxidoreductase 1 alpha
Location	14q22.1
Locus type	gene with protein product
Status	Approved
Aliases	ERO1-alpha, Ero1alpha
Ensembl gene	ENSG00000197930
Ensembl biotype	protein_coding
OMIM	615435
Entrez	30001

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay

ENST00000395686, ENST00000553714, ENST00000554019, ENST00000554251, ENST00000555069, ENST00000556039, ENST00000556223, ENST00000556358, ENST00000556769, ENST00000557178, ENST00000629528, ENST00000910737, ENST00000910738, ENST00000964628, ENST00000964629, ENST00000964630

RefSeq mRNA: 14 — MANE Select: NM_014584 NM_001382464, NM_001382465, NM_001382466, NM_001382467, NM_001382468, NM_001382469, NM_001382470, NM_001382471, NM_001382472, NM_001382473, NM_001382474, NM_001382475, NM_001382476, NM_014584

CCDS: CCDS9709

Canonical transcript exons

ENST00000395686 — 16 exons

Exon	Start	End
ENSE00000657428	52666375	52666495
ENSE00000657429	52671630	52671703
ENSE00000657430	52671795	52671871
ENSE00000657431	52682325	52682408
ENSE00000657432	52683788	52683907
ENSE00000854747	52663801	52663847
ENSE00001002743	52678434	52678472
ENSE00001376586	52639915	52643630
ENSE00003468165	52658124	52658150
ENSE00003486022	52653069	52653315
ENSE00003499749	52657917	52658009
ENSE00003503850	52646375	52646461
ENSE00003581639	52661293	52661304
ENSE00003596445	52652239	52652308
ENSE00003691200	52646154	52646287
ENSE00003849768	52695368	52695558

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 99.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.3678 / max 1204.8596, expressed in 1815 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143261	17.9776	1802
143262	8.9022	1767
143257	6.7675	1329
143258	4.1198	1266
143259	1.2052	650
143260	0.3268	167
143256	0.0687	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	99.75	gold quality
lower esophagus mucosa	UBERON:0035834	99.49	gold quality
epithelium of esophagus	UBERON:0001976	98.60	gold quality
oral cavity	UBERON:0000167	98.18	gold quality
buccal mucosa cell	CL:0002336	98.14	gold quality
esophagus mucosa	UBERON:0002469	97.69	gold quality
pharyngeal mucosa	UBERON:0000355	97.66	gold quality
body of tongue	UBERON:0011876	96.74	gold quality
pericardium	UBERON:0002407	96.59	gold quality
tonsil	UBERON:0002372	96.50	gold quality
gingiva	UBERON:0001828	95.75	gold quality
amniotic fluid	UBERON:0000173	95.61	gold quality
islet of Langerhans	UBERON:0000006	95.01	gold quality
vena cava	UBERON:0004087	94.99	gold quality
secondary oocyte	CL:0000655	94.88	gold quality
colonic epithelium	UBERON:0000397	94.87	gold quality
gingival epithelium	UBERON:0001949	94.75	gold quality
vagina	UBERON:0000996	93.64	gold quality
monocyte	CL:0000576	93.36	gold quality
palpebral conjunctiva	UBERON:0001812	93.04	gold quality
tongue	UBERON:0001723	92.97	gold quality
squamous epithelium	UBERON:0006914	92.90	gold quality
calcaneal tendon	UBERON:0003701	92.76	gold quality
mouth mucosa	UBERON:0003729	92.73	gold quality
stromal cell of endometrium	CL:0002255	92.68	gold quality
mononuclear cell	CL:0000842	92.57	gold quality
leukocyte	CL:0000738	92.43	gold quality
epithelium of nasopharynx	UBERON:0001951	92.28	gold quality
blood	UBERON:0000178	92.15	gold quality
minor salivary gland	UBERON:0001830	92.12	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-7	yes	11473.95
E-ENAD-21	yes	11298.74
E-HCAD-1	yes	2853.93
E-MTAB-10283	yes	564.59
E-GEOD-75140	no	1280.45
E-MTAB-8530	no	996.14
E-CURD-89	no	373.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DDIT3, PPARG

miRNA regulators (miRDB)

177 targeting ERO1A, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
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-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4650-5P	99.98	64.69	999

Literature-anchored findings (GeneRIF, showing 40)

• oxygen regulation of ERO1-Lalpha expression likely is to maintain the transfer rate of oxidizing equivalents to PDI in situations of an altered cellular redox state induced by changes of the cellular oxygen tension (PMID:12752442)
• two conserved cysteine triads in human Ero1alpha cooperate for efficient disulfide bond formation in the endoplasmic reticulum (PMID:15136577)
• glutathione limits Ero1-dependent oxidation in the endoplasmic reticulum (PMID:15161913)
• Hypoxic induction of Ero1-L alpha is key adaptive response in a previously unrecognized HIF-1-mediated pathway that operates to improve protein secretion under hypoxia and might be used for inhibiting tumor growth via inhibiting VEGF-driven angiogenesis. (PMID:15592500)
• Ero1alpha and Ero1beta are retained in the endoplasmic reticulum by interactions with PDI and ERp44 (PMID:16677073)
• Results determine the redox-driven shutdown mechanism of Ero1alpha from the formation of a disulphide bond between the active-site Cys(94) and Cys(131). (PMID:18833192)
• Data suggest that partial regulatory disulfide reduction may be a mechanism for preventing excessive Ero1alpha activity and oxidation of PDI or that additional factors are required for Ero1alpha activation within the mammalian ER. (PMID:18971943)
• In this report, the structural model of human Ero1-L alpha was built at first. (PMID:19766098)
• proving that the activity of Ero1-Lalpha results in H(2)O(2) formation in the endoplasmic reticulum (PMID:20095866)
• an appropriate Ero1alpha-PDI ratio is critical for regulating the binding-release cycle of CTA1 by PDI during retro-translocation, and PDI’s redox state has a role in targeting it to the retro-translocon (PMID:20130085)
• Results show that within the ER, Ero1alpha is almost exclusively found on the mitochondria-associated membrane (MAM). (PMID:20186508)
• Ero1alpha is expressed on blood platelets in association with protein-disulfide isomerase and contributes to redox-controlled remodeling of alphaIIbbeta3. (PMID:20562109)
• The results demonstrate that the specificity of Ero1alpha toward the active sites of PDI requires the presence of the regulatory disulfides. (PMID:20657012)
• A dynamic equilibrium between Ero1- and glutathione disulphide-mediated oxidation of protein disulphide isomerases constitutes an important element of endoplasmic reticulum redox homeostasis. (PMID:20802462)
• Ero1alpha limits its oxidative activity using four regulatory cysteines properly positioned within a critical loop that transfers electrons from protein disulphide isomerase to the FAD-containing active site. (PMID:20834232)
• Molecular bases of cyclic and specific disulfide interchange between human ERO1alpha protein and protein-disulfide isomerase (PDI). (PMID:21398518)
• the intramolecular electron transfer from the a domain to the a’ domain within PDI during its oxidation by ERO1alpha. (PMID:21757736)
• the levels, subcellular localization, and activity of Ero1alpha coordinately regulate Ca(2+) and redox homeostasis and signaling in the early secretory compartment. (PMID:21854214)
• hyperoxidation generated by Ero1alpha-C104A/C131A is addressed in the ER lumen and is unlikely to exert oxidative injury throughout the cell. (PMID:23027870)
• Report on the establishment of an engineered CHOS cell line that has been engineered to express both XBP-1S) and ERO1-Lalpha and has been named CHOS-XE. CHOS-XE cells produced increased antibody (MAb) yields (5.3- 6.2 fold) in comparison to CHOS cells. (PMID:23335490)
• The high expression of Ero1alpha in cancers of the esophagus and stomach demonstrates the importance of ER redox regulation in the gastro-intestinal (GI) tract in health and disease. (PMID:23373818)
• This paper reported the interactions of Ero1 with protein disulfide isomerase family proteins and chaperones, highlighting the effect that redox flux has on Ero1 partnerships. (PMID:23530257)
• The expression of hERO1-alpha in cancer cells is associated with poorer prognosis. (PMID:23578220)
• GPx7 promotes oxidative protein folding, directly utilizing Ero1alpha-generated hydrogen peroxide in the early secretory compartment. (PMID:23919619)
• Data indicate that protein disulfide isomerase (PDI) and ERp44 dynamically localize Ero1alpha and peroxiredoxin 4 in early secretory compartment (ESC). (PMID:23979138)
• ER stress induced by misfolded proinsulin was limited by increased expression of Ero1alpha, suggesting that enhancing the oxidative folding of proinsulin may be a viable therapeutic strategy in the treatment of type 2 diabetes. (PMID:24022479)
• A simple feedback mechanism of regulation of Ero1alpha was identified involving its primary substrate. (PMID:24758166)
• These results indicate that BPA, a widely distributed and potentially harmful chemical, inhibits Ero1-PDI-mediated disulfide bond formation. (PMID:25122773)
• PDI has a role as a competent regulator and a specific substrate of Ero1alpha govern efficient and faithful oxidative protein folding and maintain the ER redox homeostasis (PMID:25258311)
• Data suggest that expression of ERO1alpha (oxidoreductin-1-L-alpha) and CHOP (c/EBP-homologous protein) is up-regulated in liver of patients with acute liver failure. (PMID:25387528)
• These results suggest that overexpression of ERO1-alpha in the tumor inhibits the T cell response by recruiting polymorphonuclear myeloid-derived suppressor cells (PMID:25595776)
• the cancer-associated ERO1-alpha regulates the expression of the MHC class I molecule via oxidative folding (PMID:25870246)
• Data indicate a new mechanism of Ero1alpha regulation in which thiol-disulfide exchange at Cys208-Cys241 affects the stability of the Cys94-Cys131 inhibitory disulfide through allosteric and/or inter-molecular communication. (PMID:26609561)
• High expression of ERO1L is associated with poor prognosis of patients with gastric cancer. These results indicate that ERO1L expression may be a clinically promising therapeutic target for prevention of gastric cancer. (PMID:26987398)
• Expression of ERO1-alpha in MDA-MB-231 cells promotes tumour growth via promoting angiogenesis. Knockdown of ERO1-alpha inhibits secretion of VEGF by inhibition of oxidative protein folding. In triple-negative breast cancer cases, the expression of ERO1-alpha was upregulated and related to the number of the blood vessels. ERO1-alpha was a poor prognosis factor in triple-negative breast cancer. (PMID:27100727)
• Study shows that ERO1L and NARS expression level are up-regulated in primary lung adenocarcinoma and identifies them with a potential to promote tumor metastasis and growth of cancer cells. (PMID:27161446)
• a mechanism of dual Ero1alpha regulation by dynamic redox interactions between PDI and the two Ero1alpha flexible loops that harbor the regulatory cysteines. (PMID:27703014)
• FBXO6 as a functional E3 ubiquitin ligase for Ero1L that plays a critical role in inhibiting endoplasmic reticulum stress-induced apoptosis. (PMID:27855403)
• Authors investigated the influence of ERO1-alpha on expression of PD-L1 and immune escape and demonstrated that ERO1-alpha augmented the expression of PD-L1 via facilitation of oxidative protein folding within PD-L1. Authors showed that overexpression of ERO1-alpha increased HIF-1alpha protein expression, resulting in an increase of PD-L1 mRNA as well as protein. (PMID:28160557)
• ERO1alpha plays a crucial role in HSC proliferation via posttranslational modification of collagen and MT1-MMP (PMID:28774960)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ero1a	ENSDARG00000015228
mus_musculus	Ero1a	ENSMUSG00000021831
rattus_norvegicus	Ero1a	ENSRNOG00000006462
drosophila_melanogaster	Ero1L	FBGN0261274
caenorhabditis_elegans	ero-1	WBGENE00001334

Paralogs (1): ERO1B (ENSG00000086619)

Protein

Protein identifiers

ERO1-like protein alpha — Q96HE7 (reviewed: Q96HE7)

Alternative names: Endoplasmic oxidoreductin-1-like protein, Endoplasmic reticulum oxidoreductase alpha, Oxidoreductin-1-L-alpha

All UniProt accessions (5): G3V2H0, Q96HE7, G3V3E6, G3V503, G3V5B3

UniProt curated annotations — full annotation on UniProt →

Function. Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum. Efficiently reoxidizes P4HB/PDI, the enzyme catalyzing protein disulfide formation, in order to allow P4HB to sustain additional rounds of disulfide formation. Following P4HB reoxidation, passes its electrons to molecular oxygen via FAD, leading to the production of reactive oxygen species (ROS) in the cell. Required for the proper folding of immunoglobulins. Plays an important role in ER stress-induced, CHOP-dependent apoptosis by activating the inositol 1,4,5-trisphosphate receptor IP3R1. Involved in the release of the unfolded cholera toxin from reduced P4HB/PDI in case of infection by V.cholerae, thereby playing a role in retrotranslocation of the toxin.

Subunit / interactions. Predominantly monomer. May function both as a monomer and a homodimer. Interacts with PDILT. Interacts with ERP44; the interaction results in retention of ERO1A in the endoplasmic reticulum.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus lumen. Secreted. Cell projection. Dendrite.

Tissue specificity. Widely expressed at low level. Expressed at high level in upper digestive tract. Highly expressed in esophagus. Weakly expressed in stomach and duodenum.

Post-translational modifications. N-glycosylated. The Cys-94/Cys-99 and Cys-394/Cys-397 disulfide bonds constitute the redox-active center. The Cys-94/Cys-99 disulfide bond may accept electron from P4HB and funnel them to the active site disulfide Cys-394/Cys-397. The regulatory Cys-99/Cys-104 disulfide bond stabilizes the other regulatory bond Cys-94/Cys-131. Phosphorylated on Ser-145 by FAM20C in the Golgi which increases its enzymatic activity. Phosphorylation is induced by lactation. It is also induced by hypoxia and reductive stress.

Activity regulation. Enzyme activity is tightly regulated to prevent the accumulation of reactive oxygen species in the endoplasmic reticulum. Reversibly down-regulated by the formation of disulfide bonds between the active site Cys-94 and Cys-131, and between Cys-99 and Cys-104. Glutathione may be required to regulate its activity in the endoplasmic reticulum.

Induction. Stimulated by hypoxia; suggesting that it is regulated via the HIF-pathway.

Similarity. Belongs to the EROs family.

RefSeq proteins (14): NP_001369393, NP_001369394, NP_001369395, NP_001369396, NP_001369397, NP_001369398, NP_001369399, NP_001369400, NP_001369401, NP_001369402, NP_001369403, NP_001369404, NP_001369405, NP_055399* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007266	Ero1	Family
IPR037192	ERO1-like_sf	Homologous_superfamily

Pfam: PF04137

Catalyzed reactions (Rhea), 2 shown:

• 2 R’C(R)SH + O2 = R’C(R)S-S(R)CR’ + H2O2 (RHEA:17357)
• [protein]-dithiol + O2 = [protein]-disulfide + H2O2 (RHEA:59116)

UniProt features (68 total): mutagenesis site 18, helix 17, strand 10, disulfide bond 8, binding site 7, modified residue 3, glycosylation site 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3AHQ	X-RAY DIFFRACTION	2.35
3AHR	X-RAY DIFFRACTION	3.07

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HE7-F1	76.55	0.36

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (7): 187; 189; 200; 252; 255; 287; 300

Post-translational modifications (3): 143, 145, 106

Disulfide bonds (8): 35–48, 37–46, 85–391, 94–131, 94–99, 99–104, 208–241, 394–397

Glycosylation sites (2): 280, 384

Mutagenesis-validated functional residues (18):

Position	Phenotype
85	alters protein folding and stability. loss of regulatory disulfide bond formation and increased activity towards p4hb; w
85	induces a decrease in activity.
94	induces a decrease in activity towards thioredoxin. loss of activity towards thioredoxin and loss of regulatory disulfid
99	acts as a weak dominant-negative mutant. loss of activity towards thioredoxin. loss of regulatory disulfide bond formati
104	no effect. strongly increased activity towards p4hb and upr induction, but no broad oxidative injury; when associated wi
104	no effect.
131	loss of regulatory disulfide bond formation and increased activity towards p4hb. loss of regulatory disulfide bond forma
145	abolishes phosphorylation. does not affect interaction with erp44.
145	phosphomimetic mutant. does not affect interaction with erp44. shows two-fold increase in enzyme activity. accelerates i
166	no effect.
208	no effect.
241	no effect.
280	no effect on activity.
384	no effect on activity.
391	alters protein folding. prevents formation of regulatory disulfide bond and down-regulation of activity. decreases assoc
394	retains activity towards p4hb. does not act as a dominant negative mutant. induces defects in folding. remains associate
395	increased catalytical activity.
397	acts as a dominant negative mutant; does not induce defects in folding; remains associated with p4hb.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3299685	Detoxification of Reactive Oxygen Species

MSigDB gene sets: 289 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_MUSCLE_TISSUE_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, MENSE_HYPOXIA_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOBP_MONOATOMIC_CATION_TRANSPORT, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_UP, WEI_MYCN_TARGETS_WITH_E_BOX, MARTINEZ_RB1_TARGETS_UP

GO Biological Process (19): protein folding (GO:0006457), response to oxidative stress (GO:0006979), transforming growth factor beta receptor signaling pathway (GO:0007179), skeletal muscle tissue development (GO:0007519), response to temperature stimulus (GO:0009266), L-ascorbic acid metabolic process (GO:0019852), collagen fibril organization (GO:0030199), endoplasmic reticulum unfolded protein response (GO:0030968), protein folding in endoplasmic reticulum (GO:0034975), response to endoplasmic reticulum stress (GO:0034976), cell redox homeostasis (GO:0045454), brown fat cell differentiation (GO:0050873), release of sequestered calcium ion into cytosol (GO:0051209), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), cellular response to hypoxia (GO:0071456), apoptotic process (GO:0006915), extracellular matrix organization (GO:0030198), protein modification process (GO:0036211), protein maturation (GO:0051604)

GO Molecular Function (5): protein-disulfide reductase activity (GO:0015035), thiol oxidase activity (GO:0016972), FAD binding (GO:0071949), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (11): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), Golgi lumen (GO:0005796), membrane (GO:0016020), dendrite (GO:0030425), intracellular membrane-bounded organelle (GO:0043231), extracellular region (GO:0005576), Golgi apparatus (GO:0005794), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to chemical stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to endoplasmic reticulum stress	2
cellular response to stress	2
protein metabolic process	2
disulfide oxidoreductase activity	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
intracellular organelle lumen	2
cellular process	1
protein maturation	1
response to stress	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
striated muscle tissue development	1
skeletal muscle organ development	1
response to abiotic stimulus	1
monosaccharide metabolic process	1
carboxylic acid metabolic process	1
lactone metabolic process	1
extracellular matrix organization	1
cellular response to unfolded protein	1
intracellular signal transduction	1
protein folding	1
cellular homeostasis	1
fat cell differentiation	1
intercellular transport	1
calcium ion transmembrane import into cytosol	1
intrinsic apoptotic signaling pathway	1
response to hypoxia	1
cellular response to decreased oxygen levels	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
extracellular structure organization	1
external encapsulating structure organization	1
macromolecule modification	1
gene expression	1
catalytic activity, acting on a protein	1
oxidoreductase activity, acting on a sulfur group of donors, oxygen as acceptor	1

Protein interactions and networks

STRING

1475 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERO1A	ERP44	Q9BS26	994
ERO1A	DDIT3	P35638	800
ERO1A	HSPA5	P11021	767
ERO1A	P4HB	P07237	767
ERO1A	TXNDC5	Q8NBS9	748
ERO1A	ERN1	O75460	732
ERO1A	PPP1R15A	O75807	726
ERO1A	ITPR1	Q14643	726
ERO1A	XBP1	P17861	722
ERO1A	ATF6	P18850	703
ERO1A	EIF2S1	P05198	689
ERO1A	CANX	P27824	670
ERO1A	JCHAIN	P01591	661
ERO1A	TXN	P10599	650
ERO1A	PDIA3	P30101	633

IntAct

53 interactions, top by confidence:

A	B	Type	Score
ERO1A	PDIA3	psi-mi:“MI:0915”(physical association)	0.670
PDIA3	ERO1A	psi-mi:“MI:0408”(disulfide bond)	0.670
P4HB	ERO1A	psi-mi:“MI:0915”(physical association)	0.660
ERP44	TGFB1	psi-mi:“MI:0914”(association)	0.640
ERO1A	APPBP2	psi-mi:“MI:0915”(physical association)	0.560
APPBP2	ERO1A	psi-mi:“MI:0915”(physical association)	0.560
LHX4	ERO1A	psi-mi:“MI:0915”(physical association)	0.560
COL1A1	PDIA4	psi-mi:“MI:0914”(association)	0.560
ERO1A		psi-mi:“MI:0915”(physical association)	0.550
ERO1B	ATP4A	psi-mi:“MI:0914”(association)	0.530
ERP44	MEX3A	psi-mi:“MI:0914”(association)	0.530
LACRT	PLXNA2	psi-mi:“MI:0914”(association)	0.530
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500
COL1A1	GOLIM4	psi-mi:“MI:0915”(physical association)	0.500
EBF1	ERO1A	psi-mi:“MI:0915”(physical association)	0.490
TNIK	ERO1A	psi-mi:“MI:0915”(physical association)	0.400
ERO1A	PDIA4	psi-mi:“MI:0915”(physical association)	0.400
ERO1A	PELI2	psi-mi:“MI:0915”(physical association)	0.370
TANK	CNOT1	psi-mi:“MI:0914”(association)	0.350
FBXO6	GNS	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
lpqN	SOWAHD	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
H2AX	ANXA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (176): ERO1L (Two-hybrid), ERO1L (Affinity Capture-MS), ERO1L (Co-fractionation), ERO1L (Affinity Capture-MS), ERO1L (Proximity Label-MS), ERO1L (Proximity Label-MS), ERO1L (Affinity Capture-Western), ERO1L (Reconstituted Complex), GPX7 (PCA), GPX8 (PCA), ERO1L (Affinity Capture-MS), ERO1L (Two-hybrid), ERO1L (Affinity Capture-MS), ERO1L (Affinity Capture-MS), ERO1L (Affinity Capture-MS)

ESM2 similar proteins: A5PJN2, B1H1F9, B4URD6, B6CVD7, O18823, O43556, O43909, O56140, O70258, P0C152, P28039, P97259, Q01H84, Q08834, Q09328, Q28F39, Q29S03, Q2F4V2, Q4R5B1, Q5HYA8, Q5RAP2, Q6AXF6, Q6DD71, Q6DPZ9, Q6DQ19, Q6DQ21, Q6J8E7, Q6YAT4, Q7SEY9, Q7T3D1, Q7X9I4, Q7YTU4, Q86YB8, Q8BR76, Q8IZ81, Q8NBP0, Q8QPL1, Q8R180, Q8R2E9, Q8R3N6

Diamond homologs: A5PJN2, B1H1F9, B6CVD7, O74401, Q03103, Q6DD71, Q75BB5, Q7SEY9, Q7T3D1, Q7X9I4, Q7YTU4, Q86YB8, Q8NIP5, Q8R180, Q8R2E9, Q8R4A1, Q96HE7, Q9C7S7, Q9V3A6, Q9Y7P1

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ERO1A	“up-regulates quantity by stabilization”	ERP44	binding
FBXO6	“down-regulates quantity by destabilization”	ERO1A	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	ERO1A	polyubiquitination
FAM20C	“up-regulates activity”	ERO1A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 52 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.

GO biological processes:

GO term	Partners	Fold	FDR
response to endoplasmic reticulum stress	6	22.2×	7e-05
protein folding	7	16.1×	7e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	0
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

2008 predictions. Top by Δscore:

Variant	Effect	Δscore
14:52646149:CTAA:C	donor_loss	1.0000
14:52646150:TAA:T	donor_loss	1.0000
14:52646153:C:T	donor_loss	1.0000
14:52646283:TGAGT:T	acceptor_gain	1.0000
14:52646284:GAGT:G	acceptor_gain	1.0000
14:52646286:GT:G	acceptor_gain	1.0000
14:52646288:C:CA	acceptor_loss	1.0000
14:52646288:C:CC	acceptor_gain	1.0000
14:52646289:T:C	acceptor_loss	1.0000
14:52646369:GCTTA:G	donor_loss	1.0000
14:52646370:CTTAC:C	donor_loss	1.0000
14:52646371:TTAC:T	donor_loss	1.0000
14:52646372:TACCT:T	donor_loss	1.0000
14:52646373:A:C	donor_loss	1.0000
14:52646374:C:CA	donor_loss	1.0000
14:52646461:CCTGA:C	acceptor_loss	1.0000
14:52646462:C:A	acceptor_loss	1.0000
14:52646463:T:G	acceptor_loss	1.0000
14:52653067:A:AC	donor_gain	1.0000
14:52653068:C:CC	donor_gain	1.0000
14:52653113:AT:A	donor_gain	1.0000
14:52653114:T:TA	donor_gain	1.0000
14:52653221:AAG:A	donor_gain	1.0000
14:52653221:AAGC:A	donor_gain	1.0000
14:52663977:AGTTT:A	donor_gain	1.0000
14:52666371:ATACT:A	donor_loss	1.0000
14:52666372:TAC:T	donor_loss	1.0000
14:52666373:A:AC	donor_gain	1.0000
14:52666373:A:T	donor_loss	1.0000
14:52666374:C:CA	donor_gain	1.0000

AlphaMissense

3111 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:52643618:A:C	S453R	0.999
14:52643618:A:T	S453R	0.999
14:52643620:T:G	S453R	0.999
14:52657954:G:C	S257R	0.999
14:52657954:G:T	S257R	0.999
14:52657956:T:G	S257R	0.999
14:52666404:C:A	W200C	0.999
14:52666404:C:G	W200C	0.999
14:52666406:A:G	W200R	0.999
14:52666406:A:T	W200R	0.999
14:52646265:A:G	L412P	0.998
14:52646281:C:G	G407R	0.998
14:52646389:A:G	W400R	0.998
14:52646389:A:T	W400R	0.998
14:52646397:C:G	C397S	0.998
14:52646398:A:G	C397R	0.998
14:52646398:A:T	C397S	0.998
14:52646407:A:G	C394R	0.998
14:52646414:A:C	C391W	0.998
14:52646415:C:T	C391Y	0.998
14:52646416:A:G	C391R	0.998
14:52653189:A:G	L312P	0.998
14:52657964:A:G	L254P	0.998
14:52657967:C:T	G253D	0.998
14:52646274:C:T	G409D	0.997
14:52646387:C:A	W400C	0.997
14:52646387:C:G	W400C	0.997
14:52646391:A:G	L399P	0.997
14:52646405:A:C	C394W	0.997
14:52646415:C:A	C391F	0.997

dbSNP variants (sampled 300 via entrez): RS1000020058 (14:52662897 G>A,C), RS1000113116 (14:52689332 C>A), RS1000125724 (14:52654868 C>G), RS1000128729 (14:52669421 C>A), RS1000138668 (14:52697280 G>A,T), RS1000229739 (14:52689106 C>A), RS1000262350 (14:52688762 C>G), RS1000391554 (14:52651841 A>C), RS1000433033 (14:52682545 G>A), RS1000479560 (14:52669771 T>A), RS1000659724 (14:52651288 A>C,G), RS1000678895 (14:52695433 G>A,C,T), RS1000868735 (14:52682200 C>T), RS1000871402 (14:52639832 G>T), RS1000939161 (14:52677459 G>C)

Disease associations

OMIM: gene MIM:615435 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001942_15	Prostate cancer	2.000000e-14
GCST006979_1046	Heel bone mineral density	2.000000e-11
GCST010559_2	Urine 6-bromotryptophan levels in chronic kidney disease	3.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0005116	urinary metabolite measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1671609 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

6 potent at pChembl≥5 of 17 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.48	Kd	330.1	nM	CHEMBL5653589
6.48	ED50	330.1	nM	CHEMBL5653589
5.52	IC50	3000	nM	CHEMBL1668289
5.10	IC50	8000	nM	CHEMBL1668291
5.00	IC50	1e+04	nM	MOLIBRESIB
5.00	IC50	1e+04	nM	CHEMBL1668295

PubChem BioAssay actives

5 with measured affinity, of 30 total; 5 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	2148338: Binding affinity to human ERO1L incubated for 45 mins by Kinobead based pull down assay	kd	0.3301	uM
[2-bromo-4-[(E)-[1-(4-bromophenyl)-3,5-dioxopyrazolidin-4-ylidene]methyl]-6-methoxyphenyl] acetate	568284: Inhibition of human Ero1-Lalpha	ic50	3.0000	uM
(4E)-2-(4-chlorophenyl)-4-[(3,4-dimethoxyphenyl)methylidene]-5-(trifluoromethyl)pyrazol-3-one	568284: Inhibition of human Ero1-Lalpha	ic50	8.0000	uM
2-(4,5-dinitroimidazol-1-yl)-N-(3-nitro-5-phenoxyphenyl)acetamide	568284: Inhibition of human Ero1-Lalpha	ic50	10.0000	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179066: Inhibition of ERO1L (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases methylation, affects cotreatment	8
Cyclosporine	decreases expression, increases expression	5
Oxygen	increases expression	3
2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide	increases expression, decreases reaction	2
bisphenol A	decreases expression, affects expression	2
arsenite	decreases reaction, increases expression	2
cobaltous chloride	increases expression	2
Zoledronic Acid	increases expression	2
Diethylhexyl Phthalate	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
NMS-873	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
parthenolide	decreases expression	1
chloroacetaldehyde	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	increases abundance, increases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	increases expression	1
hydroxyhydroquinone	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
tetrathiomolybdate	decreases expression	1
zinc chromate	increases abundance, increases expression	1
ochratoxin A	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
adefovir dipivoxil	increases expression	1
deguelin	increases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1670746	Binding	Inhibition of human Ero1-Lalpha	Identification of small molecular inhibitors for Ero1p by structure-based virtual screening. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E8IB	CHOK1-E	Spontaneously immortalized cell line	Female
CVCL_Y012	CHOS-XE	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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