NACA Gene

Name	nascent polypeptide-associated complex alpha subunit
Description	This gene encodes a protein that associates with basic transcription factor 3 (BTF3) to form the nascent polypeptide-associated complex (NAC). This complex binds to nascent proteins that lack a signal peptide motif as they emerge from the ribosome, blocking interaction with the signal recognition particle (SRP) and preventing mistranslocation to the endoplasmic reticulum. This protein is an IgE autoantigen in atopic dermatitis patients. Alternative splicing results in multiple transcript variants, but the full length nature of some of these variants, including those encoding very large proteins, has not been determined. There are multiple pseudogenes of this gene on different chromosomes. [provided by RefSeq, Feb 2016]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNACA, the alpha‐subunit of the nascent polypeptide–associated complex (NAC), is a conserved ribosome‐bound factor that plays a dual role in protein homeostasis. In its canonical function, NACA associates with its beta–subunit to bind emerging nascent chains at the ribosomal exit tunnel, thereby preventing their mistargeting and promoting proper folding. Structural studies have revealed that the human NAC domain contains a distinct nucleic acid–binding region that can be unmasked under certain conditions, and recent work demonstrates that NACA (and specifically the N terminus of βNAC) also exhibits potent ribosome–independent chaperone activity—suppressing aggregation of misfolded proteins and polyglutamine–expanded species implicated in neurodegenerative diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in co–translational protein maturation, NACA functions as a versatile transcriptional co–regulator with prominent tissue–specific isoforms. A muscle–specific splice variant, often termed skNAC, binds defined DNA elements to activate promoters such as that of myoglobin, thereby accelerating myogenic differentiation and myoblast fusion; reconstitution of skNAC expression in rhabdomyosarcoma cells even reduces their proliferative and metastatic potential. In hematopoietic progenitors, NACA is essential for erythroid differentiation by promoting hemoglobin production, while in osteoblasts it partners with key transcription factors including c–JUN and ATF4 to modulate genes critical for bone formation. In addition, altered NACA expression has been reported in neurological disorders—as observed in Alzheimer’s disease and Down syndrome—and NACA has been identified as an IgE–reactive autoantigen in atopic dermatitis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNACA also plays critical roles in cellular stress responses and survival pathways. Under hypoxic conditions, activation of glycogen synthase kinase–3β triggers the degradation of αNAC, leading to endoplasmic reticulum stress and subsequent apoptosis—a mechanism that underscores its involvement in oxygen–sensing pathways. Consistent with this, NACA interacts with proteins such as PHD2 that cotranslationally modify hypoxia–inducible factor α, thereby influencing erythropoiesis. In cancer cells, intact αNAC exerts anti–apoptotic functions by engaging the FADD/c–JUN N–terminal kinase cascade and, conversely, its depletion sensitizes cells to apoptotic agents; however, analyses in conditions such as juvenile myelomonocytic leukemia and certain thyroid neoplasms indicate that aberrant regulation of NACA does not uniformly impact all tumor types."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yiwei Liu, Yingxia Hu, Xu Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The crystal structure of the human nascent polypeptide-associated complex domain reveals a nucleic acid-binding region on the NACA subunit ."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi902050p"}], "href": "https://doi.org/10.1021/bi902050p"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20214399"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20214399"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Koning Shen, Martin Gamerdinger, Rebecca Chan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2019.03.012"}], "href": "https://doi.org/10.1016/j.molcel.2019.03.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30982745"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30982745"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "W V Yotov, R St-Arnaud "}, {"type": "b", "children": [{"type": "t", "text": "Differential splicing-in of a proline-rich exon converts alphaNAC into a muscle-specific transcription factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (1996)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.10.14.1763"}], "href": "https://doi.org/10.1101/gad.10.14.1763"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "8698236"}], "href": "https://pubmed.ncbi.nlm.nih.gov/8698236"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Seong Hwan Kim, Ki Shuk Shim, Gert Lubec "}, {"type": "b", "children": [{"type": "t", "text": "Human brain nascent polypeptide-associated complex alpha subunit is decreased in patients with Alzheimer' s disease and Down syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Investig Med (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2310/6650.2002.33287"}], "href": "https://doi.org/10.2310/6650.2002.33287"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12109594"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12109594"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Roschanak Mossabeb, Susanne Seiberler, Irene Mittermann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of a novel isoform of alpha-nascent polypeptide-associated complex as IgE-defined autoantigen."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1046/j.1523-1747.2002.00518.x"}], "href": "https://doi.org/10.1046/j.1523-1747.2002.00518.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12406326"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12406326"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sophie Lopez, Laetitia Stuhl, Serge Fichelson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NACA is a positive regulator of human erythroid-cell differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.02295"}], "href": "https://doi.org/10.1242/jcs.02295"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15784678"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15784678"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "René St-Arnaud, Bahareh Hekmatnejad "}, {"type": "b", "children": [{"type": "t", "text": "Combinatorial control of ATF4-dependent gene transcription in osteoblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann N Y Acad Sci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1749-6632.2011.06197.x"}], "href": "https://doi.org/10.1111/j.1749-6632.2011.06197.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22082360"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22082360"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Janine Berkholz, Weronika Kuzyniak, Michael Hoepfner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of the skNAC gene in human rhabdomyosarcoma cells enhances their differentiation potential and inhibits tumor cell growth and spreading."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Exp Metastasis (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10585-014-9676-z"}], "href": "https://doi.org/10.1007/s10585-014-9676-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25209525"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25209525"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "William N Addison, Martin Pellicelli, René St-Arnaud "}, {"type": "b", "children": [{"type": "t", "text": "Dephosphorylation of the transcriptional cofactor NACA by the PP1A phosphatase enhances cJUN transcriptional activity and osteoblast differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA118.006920"}], "href": "https://doi.org/10.1074/jbc.RA118.006920"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30948508"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30948508"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Klaus Hämmerle, Parviz Shayan, Charlotte M Niemeyer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression analysis of alpha-NAC and ANX2 in juvenile myelomonocytic leukemia using SMART polymerase chain reaction and \"virtual Northern\" hybridization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Genet Cytogenet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0165-4608(02)00841-5"}], "href": "https://doi.org/10.1016/s0165-4608(02"}, {"type": "t", "text": "00841-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12699894"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12699894"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Y Hotokezaka, K van Leyen, E H Lo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "alphaNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cdd.2009.90"}], "href": "https://doi.org/10.1038/cdd.2009.90"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19609276"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19609276"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Yusuf Ziya Igci, Ahmet Arslan, Ersin Akarsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential expression of a set of genes in follicular and classic variants of papillary thyroid carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocr Pathol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12022-011-9157-8"}], "href": "https://doi.org/10.1007/s12022-011-9157-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21509594"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21509594"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "W Zeng, J Zhang, M Qi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "αNAC inhibition of the FADD-JNK axis plays anti-apoptotic role in multiple cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cddis.2014.192"}], "href": "https://doi.org/10.1038/cddis.2014.192"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24901053"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24901053"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Daisheng Song, Kai Peng, Bradleigh E Palmer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.2022112059"}], "href": "https://doi.org/10.15252/embj.2022112059"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36219563"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36219563"}]}]}]}
Synonyms	SKNAC, HSD48, NAC-alpha, NACA1
Proteins	NACAM_HUMAN
NCBI Gene ID	4666
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

NACA has 11,003 functional associations with biological entities spanning 8 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) extracted from 119 datasets.

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

If available, associations are ranked by standardized value

Harmonizome 3.0

NACA 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 NACA 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 NACA 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 NACA 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 NACA 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 NACA 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 NACA 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 NACA 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 NACA 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 NACA 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 NACA 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 NACA gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of NACA 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 NACA gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with NACA gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with NACA protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with NACA 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 NACA gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of NACA 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 NACA gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of NACA gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of NACA gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing NACA protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing NACA protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with NACA 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 NACA 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 NACA gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with NACA gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with NACA gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with NACA gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of NACA protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with NACA 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 NACA 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 NACA 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 NACA gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with NACA 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 NACA 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 NACA gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of NACA 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 NACA from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of NACA gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.