ArticleAlcoholism, clinical and experimental research2017
FoxO1-AMPK-ULK1 Regulates Ethanol-Induced Autophagy in Muscle by Enhanced ATG14 Association with the BECN1-PIK3C3 Complex.
Article in Alcoholism, clinical and experimental research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 23 citations in OpenAlex.
- Alcohol Consumption During Muscle Disuse Causes Differential Signaling Responses in a Muscle-Specific Manner in Mice.International journal of molecular sciences · 2026Article
- Class III Phosphatidylinositol-3 Kinase/Vacuolar Protein Sorting 34 in Cardiovascular Health and Disease.Journal of cardiovascular translational research · 2025Review
- Transcriptional regulation of autophagy in skeletal muscle stem cells.Disease models & mechanisms · 2025Review
- Polyamines and Physical Activity in Musculoskeletal Diseases: A Potential Therapeutic Challenge.International journal of molecular sciences · 2023Review
- Article
- Induction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D.Nature communications · 2022Article
- Regulation of PGC1α Downstream of the Insulin Signaling Pathway Plays a Role in the Hepatic Proteotoxicity of Mutant α1-Antitrypsin Deficiency Variant Z.Gastroenterology · 2022Article
- Construction of PIK3C3 Transgenic Pig and Its Pathogenesis of Liver Damage.Life (Basel, Switzerland) · 2022Article
- Synbiotics Alleviate Hepatic Damage, Intestinal Injury and Muscular Beclin-1 Elevation in Rats after Chronic Ethanol Administration.International journal of molecular sciences · 2021Article
- RSK2 protects human breast cancer cells under endoplasmic reticulum stress through activating AMPKα2-mediated autophagy.Oncogene · 2020Article
- Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms.Frontiers in physiology · 2020Review
- MicroRNA-21 promotes the proliferation, migration and invasion of non-small cell lung cancer A549 cells by regulating autophagy activity via AMPK/ULK1 signaling pathway.Experimental and therapeutic medicine · 2018Article
- Mechanisms Underlying Muscle Protein Imbalance Induced by Alcohol.Annual review of nutrition · 2018Article
- Beclin 1 Phosphorylation - at the Center of Autophagy Regulation.Frontiers in cell and developmental biology · 2018Review
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4 authors at 1 institution in 1 country.
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Abstract
backgroundExcessive alcohol (EtOH) consumption causes an imbalance in protein metabolism. EtOH impairs protein synthesis in C2C12 myoblasts via a FoxO1-AMPK-TSC2-mTORC1 pathway and also induces protein degradation. As the underlying regulatory signaling cascades for these processes are currently poorly defined, we tested the hypothesis that alcohol-induced autophagy is mediated via activation of the PIK3C3 complex that is regulated by FoxO1-AMPK.
methodsC2C12 myoblasts were incubated with EtOH for various periods of time, and autophagy pathway-related proteins were assessed by Western blotting and immunoprecipitation. Expression of targeted genes was suppressed using electroporation of specific siRNAs and chemical inhibitors.
resultsIncubation of C2C12 myoblasts with 100 mM EtOH increased the autophagy markers LC3B-II and ATG7, whereas levels of SQSTM1/p62 decreased. The lysosomal inhibitor bafilomycin A1 caused a similar response, although there was no additive effect when combined with EtOH. EtOH altered ULK1 S555 and S757 phosphorylation in a time- and AMPK-dependent manner. The activation of AMPK and ULK1 was associated with increased BECN1 (S93, S14) and PIK3C3/VPS34 (S164) phosphorylation as well as increased total ATG14 and PIK3C3. These changes promoted formation of the ATG14-AMBRA1-BECN1-PIK3C3 proautophagy complex that is important in autophagosome formation. EtOH-induced changes were not associated with increased production of PtdIns3P, which may be due to enhanced PIK3C3 complex binding with 14-3-3θ. Reduction of AMPK using siRNA suppressed the stimulatory effect of EtOH on BECN1 S93, BECN1 S14, and PIK3C3 S164 phosphorylation in a time-dependent manner. Likewise, knockdown of AMPK or chemical inhibition of FoxO1 attenuated phosphorylation of ULK1 at both residues. Knockdown of ULK1 or BECN1 antagonized the effect of EtOH on LC3B-II, SQSTM1, and ATG7 protein expression.
conclusionsEtOH-induced autophagy is mediated through changes in phosphorylation and interaction of various PIK3C3 complex components. This, in turn, is regulated either directly via FoxO1-AMPK or indirectly via the FoxO1-AMPK-ULK1 signaling cascade in a mTORC1-independent or mTORC1-dependent manner.
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