PDIA6 Gene

HGNC Family	Protein disulfide isomerases (PDI)
Name	protein disulfide isomerase family A, member 6
Description	This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, two catalytically active thioredoxin (TRX) domains, a TRX-like domain, and a C-terminal ER-retention sequence. This protein inhibits the aggregation of misfolded proteins and exhibits both isomerase and chaperone activity. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPDIA6, also known as ERp5, plays a crucial extracellular role by catalyzing thiol‐disulfide exchange reactions at the cell surface. PDIA6 mediates the cleavage of disulfide bonds in membrane‐proximal regions of proteins such as MICA—thereby promoting the release of soluble immunomodulatory ligands that facilitate tumor immune evasion—and regulates the activation of integrins during platelet stimulation. In addition, PDIA6 in tumor and stromal cells contributes to the shedding of NKG2D ligands, an event that is critical for dampening cytotoxic immune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the endoplasmic reticulum, PDIA6 functions as an oxidoreductase and chaperone that assists in protein folding and modulates the unfolded protein response. Detailed biochemical studies have demonstrated that PDIA6 possesses both disulfide isomerase and substrate‐specific chaperone activities. Its dysregulation contributes to chemoresistance and tumor cell proliferation by affecting key signaling pathways—including the Wnt/β‐catenin cascade—and by modulating the stability and deubiquitination of proteins such as β‐catenin, PD-L1, and vimentin."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its enzymatic roles, emerging evidence indicates that PDIA6 is subjected to regulation by microRNAs and participates in broader cellular stress responses. In certain tumors—such as giant cell tumors of bone—downregulation of specific miRNAs leads to an upregulation of PDIA6 that supports tumor engraftment and progression. PDIA6 also impacts the unfolded protein response, and its inactivation or mutation is associated with developmental defects, diabetes, and altered primary ciliogenesis under endoplasmic reticulum stress. Intriguingly, recent studies have uncovered a novel RNA-binding activity for PDIA6 that may further contribute to its tumorigenic properties."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPDIA6 overexpression has been documented in a variety of human cancers—including non‐small cell lung cancer, oral squamous cell carcinoma, and endometrial cancer—where it promotes tumor cell stemness, aerobic glycolysis, and chemoresistance. Transcriptional regulators such as SOX2 and modulatory axes involving TGF-β have been shown to enhance PDIA6 expression and activity, thereby bolstering malignant phenotypes. Collectively, these findings identify PDIA6 as both a multifunctional enzyme within the cellular protein quality control machinery and as a potent contributor to cancer progression, thereby underscoring its potential as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Brett K Kaiser, Daesong Yim, I-Ting Chow, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "PDIA6 promotes the proliferation of HeLa cells through activating the Wnt/β-catenin signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.10795"}], "href": "https://doi.org/10.18632/oncotarget.10795"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27462866"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27462866"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yihui Ma, Peiyi Xia, Zhengyang Wang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal-onset diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cge.13930"}], "href": "https://doi.org/10.1111/cge.13930"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33495992"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33495992"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Joon Bum Kim, Hyejin Hyung, Ji-Eun Bae, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased ER stress by depletion of PDIA6 impairs primary ciliogenesis and enhances sensitivity to ferroptosis in kidney cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMB Rep (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.5483/BMBRep.2023-0247"}], "href": "https://doi.org/10.5483/BMBRep.2023-0247"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39044457"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39044457"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Neus Mestre-Farràs, Santiago Guerrero, Nadine Bley, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EBioMedicine (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ebiom.2019.03.045"}], "href": "https://doi.org/10.1016/j.ebiom.2019.03.045"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30922965"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30922965"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Ling Mao, Xiaoweng Wu, Zhengpeng Gong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PDIA6 contributes to aerobic glycolysis and cancer progression in oral squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World J Surg Oncol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12957-021-02190-w"}], "href": "https://doi.org/10.1186/s12957-021-02190-w"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33761940"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33761940"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Pengling Wang, Tianli Zhang, Nan Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PDIA6, which is regulated by TRPM2-AS/miR-424-5p axis, promotes endometrial cancer progression via TGF-beta pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-023-06297-8"}], "href": "https://doi.org/10.1038/s41419-023-06297-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38097564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38097564"}]}]}]}
Synonyms	ERP5, TXNDC7
Proteins	PDIA6_HUMAN
NCBI Gene ID	10130
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

PDIA6 has 13,241 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 127 datasets.

Click the + buttons to view associations for PDIA6 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

PDIA6 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by PDIA6 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of PDIA6 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of PDIA6 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of PDIA6 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of PDIA6 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of PDIA6 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of PDIA6 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of PDIA6 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of PDIA6 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of PDIA6 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of PDIA6 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of PDIA6 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of PDIA6 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with PDIA6 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with PDIA6 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of PDIA6 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of PDIA6 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of PDIA6 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing PDIA6 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing PDIA6 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing PDIA6 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing PDIA6 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing PDIA6 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with PDIA6 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with PDIA6 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of PDIA6 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with PDIA6 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with PDIA6 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with PDIA6 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of PDIA6 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by PDIA6 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with PDIA6 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with PDIA6 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with PDIA6 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with PDIA6 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with PDIA6 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at PDIA6 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of PDIA6 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of PDIA6 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing PDIA6 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.