Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy
| Autor: | Andrea Armani, Jihye Paik, Reimar Abraham, Bert Blaauw, Jinghui Zhao, Giulia Milan, Marco Sandri, Vanina Romanello, Alfred L. Goldberg, Ronald A. DePinho, Anke Seydel, Francesca Pescatore, Laura Frasson |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Proteasome Endopeptidase Complex DNA Repair Transcription Genetic Ubiquitin-Protein Ligases General Physics and Astronomy Cell Cycle Proteins FOXO1 Article General Biochemistry Genetics and Molecular Biology Mice Ubiquitin Autophagy medicine Animals Gene Regulatory Networks Muscle Skeletal Protein kinase B Transcription factor PI3K/AKT/mTOR pathway Mice Knockout Multidisciplinary biology Forkhead Box Protein O1 TOR Serine-Threonine Kinases Forkhead Box Protein O3 fungi Gluconeogenesis Forkhead Transcription Factors General Chemistry Muscle atrophy 3. Good health Cell biology Muscular Atrophy Gene Expression Regulation Proteasome Biochemistry Unfolded Protein Response biology.protein Female medicine.symptom Lysosomes Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Nature Communications |
| Popis: | Stresses like low nutrients, systemic inflammation, cancer or infections provoke a catabolic state characterized by enhanced muscle proteolysis and amino acid release to sustain liver gluconeogenesis and tissue protein synthesis. These conditions activate the family of Forkhead Box (Fox) O transcription factors. Here we report that muscle-specific deletion of FoxO members protects from muscle loss as a result of the role of FoxOs in the induction of autophagy–lysosome and ubiquitin–proteasome systems. Notably, in the setting of low nutrient signalling, we demonstrate that FoxOs are required for Akt activity but not for mTOR signalling. FoxOs control several stress–response pathways such as the unfolded protein response, ROS detoxification, DNA repair and translation. Finally, we identify FoxO-dependent ubiquitin ligases including MUSA1 and a previously uncharacterised ligase termed SMART (Specific of Muscle Atrophy and Regulated by Transcription). Our findings underscore the central function of FoxOs in coordinating a variety of stress-response genes during catabolic conditions. FoxO transcription factors promote muscle atrophy in response to stresses such as low nutrient availability. By generating muscle-specific FoxO triple-knockout mice, Milan et al. identify mechanisms by which the FoxO transcriptional network coordinates autophagic and proteasomal protein degradation. |
| Databáze: | OpenAIRE |
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