ArticleMolecular biology of the cell2020
The HIF target ATG9A is essential for epithelial barrier function and tight junction biogenesis.
Article in Molecular biology of the cell, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 27 citations in OpenAlex.
- BECN1 Protects Against Intestinal Ischemia/Reperfusion Injury by Promoting NLRP3 Ubiquitination and Suppressing Inflammasome Activation.Digestive diseases and sciences · 2026Article
- Metabolic host-microbe crosstalk in stabilization of epithelial HIF.Microbiome · 2026Article
- From mechanisms to therapeutics: molecular insights into gastrointestinal injury under high-altitude hypoxia.Frontiers in microbiology · 2026Review
- Progress on multifunctional transmembrane protein ATG9A.Cell communication and signaling : CCS · 2025Review
- Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery.Annals of the rheumatic diseases · 2024Article
- Targeting hypoxia-inducible factors: therapeutic opportunities and challenges.Nature reviews. Drug discovery · 2024Review
- Research Progress on the Mechanism of Intestinal Barrier Damage and Drug Therapy in a High Altitude Environment.Current drug delivery · 2024Review
- Crosstalk between hypoxia-inducible factor-1α and short-chain fatty acids in inflammatory bowel disease: key clues toward unraveling the mystery.Frontiers in immunology · 2024Review
- Mimicry of microbially-derived butyrate reveals templates for potent intestinal epithelial HIF stabilizers.Gut microbes · 2023Article
- S100a9 inhibits Atg9a transcription and participates in suppression of autophagy in cardiomyocytes induced by βCellular & molecular biology letters · 2023Article
- Hypoxia-stabilized RIPK1 promotes cell death.Nature cell biology · 2023Article
- Regulatory Functions of Hypoxia in Host-Parasite Interactions: A Focus on Enteric, Tissue, and Blood Protozoa.Microorganisms · 2023Review
- Essential role for epithelial HIF-mediated xenophagy in control of Salmonella infection and dissemination.Cell reports · 2022Article
- Hypoxia-inducible factor as a bridge between healthy barrier function, wound healing, and fibrosis.American journal of physiology. Cell physiology · 2022Review
- Regulation of autophagy fires up the cold tumor microenvironment to improve cancer immunotherapy.Frontiers in immunology · 2022Review
- A short chain fatty acid-centric view of Clostridioides difficile pathogenesis.PLoS pathogens · 2021Review
- Gut microbiota-derived metabolites as key mucosal barrier modulators in obesity.World journal of gastroenterology · 2021Review
- Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions.Trends in immunology · 2021Review
- Microbial-derived indoles inhibit neutrophil myeloperoxidase to diminish bystander tissue damage.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Intestinal epithelial cells (IECs) exist in a metabolic state of low oxygen tension termed "physiologic hypoxia." An important factor in maintaining intestinal homeostasis is the transcription factor hypoxia-inducible factor (HIF), which is stabilized under hypoxic conditions and mediates IEC homeostatic responses to low oxygen tension. To identify HIF transcriptional targets in IEC, chromatin immunoprecipitation (ChIP) was performed in Caco-2 IECs using HIF-1α- or HIF-2α-specific antibodies. ChIP-enriched DNA was hybridized to a custom promoter microarray (termed ChIP-chip). This unbiased approach identified autophagy as a major HIF-1-targeted pathway in IEC. Binding of HIF-1 to the ATG9A promoter, the only transmembrane component within the autophagy pathway, was particularly enriched by exposure of IEC to hypoxia. Validation of this ChIP-chip revealed prominent induction of ATG9A, and luciferase promoter assays identified a functional hypoxia response element upstream of the TSS. Hypoxia-mediated induction of ATG9A was lost in cells lacking HIF-1. Strikingly, we found that lentiviral-mediated knockdown (KD) of ATG9A in IECs prevents epithelial barrier formation by >95% and results in significant mislocalization of multiple tight junction (TJ) proteins. Extensions of these findings showed that ATG9A KD cells have intrinsic abnormalities in the actin cytoskeleton, including mislocalization of the TJ binding protein vasodilator-stimulated phosphoprotein. These results implicate ATG9A as essential for multiple steps of epithelial TJ biogenesis and actin cytoskeletal regulation. Our findings have novel applicability for disorders that involve a compromised epithelial barrier and suggest that targeting ATG9A may be a rational strategy for future therapeutic intervention.
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