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10 sources retrieved · Most recent: April 2026 · Index updated 14 days ago
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USF2
upstream transcription factor 2, c-fos interacting
Chromosome 19 · 19q13.12
NCBI Gene: 7392Ensembl: ENSG00000105698.17HGNC: HGNC:12594UniProt: Q15853
100PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
FUNCTIONAL ROLE
Transcription Factor
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
glucose mediated signaling pathwaypositive regulation of transcription by RNA polymerase IIDNA-binding transcription activator activity, RNA polymerase II-specificnucleoplasmneurodegenerative diseaseprostate cancerFamilial prostate cancerhepatocellular carcinoma
✦AI Summary

USF2 is a bHLH transcription factor that binds E-box elements (5'-CACGTG-3') to regulate gene expression across multiple physiological processes 1. Functionally, USF2 acts as a transcriptional repressor of autophagy and lysosomal genes under nutrient-rich conditions by recruiting HDAC1 to CLEAR motifs, thereby reducing histone acetylation and chr19 accessibility 23. During nutrient deprivation, GSK3β-mediated phosphorylation of USF2 at serine 155 weakens its DNA binding, allowing TFEB to competitively activate these genes 3. USF2 also positively regulates genes involved in pathological processes: it transcriptionally activates THBS1 to promote TGF-β/Smad3 signaling and pyroptosis in sepsis-induced acute kidney injury 4, and activates LPCAT3 to drive ferroptosis through the NRF2/HO-1/GPX4 pathway 5. Additionally, USF2 co-regulates MSI2 expression with PLAG1 in hematopoietic stem cells, controlling stem cell self-renewal 1. Clinically, USF2 inhibition represents a therapeutic strategy for protein aggregation diseases and lysosomal dysfunction 3, and USF2 reduction of β-glucocerebrosidase activity may influence Parkinson's disease risk in GBA1 mutation carriers 6.

Sources cited
1
USF2 co-regulates MSI2 transcription with PLAG1 in hematopoietic stem and progenitor cells
PMID: 29641991
2
USF2 binds CLEAR motifs with HDAC1 to repress lysosomal and autophagy genes under nutrient-rich conditions and competes with TFEB during starvation
PMID: 39333072
3
USF2 phosphorylation at S155 by GSK3β governs its DNA-binding activity in lysosomal gene repression; USF2 knockout enhances autophagy-lysosome clearance
PMID: 39936623
4
USF2 transcriptionally activates THBS1 to promote TGF-β/Smad3/NLRP3/Caspase-1 pyroptosis pathway in sepsis-induced acute kidney injury
PMID: 34756923
5
USF2 transcriptionally activates LPCAT3 to drive ferroptosis through NRF2/HO-1/GPX4 pathway in sepsis-induced acute kidney injury
PMID: 40138726
6
USF2 activation decreases lysosomal β-glucocerebrosidase activity, with implications for Parkinson's disease risk in GBA1 mutation carriers
PMID: 39438499
7
USF1 and USF2 bind E-box elements and mediate inhibition of CYP19 gene expression in human trophoblasts
PMID: 12917334
Disease Associationsⓘ20
neurodegenerative diseaseOpen Targets
0.54Moderate
prostate cancerOpen Targets
0.11Weak
Familial prostate cancerOpen Targets
0.11Weak
hepatocellular carcinomaOpen Targets
0.10Weak
gastric cancerOpen Targets
0.07Suggestive
urinary bladder carcinomaOpen Targets
0.07Suggestive
leukemiaOpen Targets
0.05Suggestive
colorectal carcinomaOpen Targets
0.05Suggestive
neoplasmOpen Targets
0.04Suggestive
cancerOpen Targets
0.04Suggestive
chronic gastritisOpen Targets
0.03Suggestive
breast angiosarcomaOpen Targets
0.03Suggestive
infectionOpen Targets
0.03Suggestive
Griscelli diseaseOpen Targets
0.03Suggestive
Griscelli disease type 1Open Targets
0.03Suggestive
Griscelli syndrome type 1Open Targets
0.03Suggestive
SepsisOpen Targets
0.03Suggestive
acute kidney injuryOpen Targets
0.03Suggestive
EndometritisOpen Targets
0.03Suggestive
salivary gland diseaseOpen Targets
0.03Suggestive
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
EP300Protein interaction89%SP1Protein interaction88%MED1Protein interaction80%BRCA1Protein interaction78%ADAMTS12Protein interaction77%USF1Protein interaction64%
Tissue Expression6 tissues
Liver
100%
Ovary
91%
Heart
77%
Lung
67%
Bone Marrow
64%
Brain
53%
Gene Interaction Network
Click a node to explore
USF2EP300SP1MED1BRCA1ADAMTS12USF1
PROTEIN STRUCTURE
Preparing viewer…
PDB8IA3 · 3.50 Å · X-ray
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
0.71LoF Tolerant
pLIⓘ
0.04Tolerant
Observed/Expected LoF0.47 [0.32–0.71]
RankingsWhere USF2 stands among ~20K protein-coding genes
  • #4,819of 20,598
    Most Researched100 · top quartile
  • #5,446of 17,882
    Most Constrained (LOEUF)0.71
Genes detectedUSF2
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
USF2 knockdown downregulates THBS1 to inhibit the TGF-β signaling pathway and reduce pyroptosis in sepsis-induced acute kidney injury.
PMID: 34756923
Pharmacol Res · 2022
1.00
2
USF2 and TFEB compete in regulating lysosomal and autophagy genes.
PMID: 39333072
Nat Commun · 2024
0.90
3
Direct and indirect regulation of β-glucocerebrosidase by the transcription factors USF2 and ONECUT2.
PMID: 39438499
NPJ Parkinsons Dis · 2024
0.80
4
PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells.
PMID: 29641991
Stem Cell Reports · 2018
0.70
5
Transcriptional repression of autophagy and lysosome biogenesis.
PMID: 39936623
Autophagy · 2025
0.60