title: Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy.
abstract: 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.
authors: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy.
authors: Giulia
authors: G
authors: Milan
authors: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy.
authors: Vanina
authors: V
authors: Romanello
authors: 1] Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy [2] Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors: Francesca
authors: F
authors: Pescatore
authors: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy.
authors: Andrea
authors: A
authors: Armani
authors: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors: Ji-Hye
authors: JH
authors: Paik
authors: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy.
authors: Laura
authors: L
authors: Frasson
authors: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy.
authors: Anke
authors: A
authors: Seydel
authors: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Jinghui
authors: J
authors: Zhao
authors: Department of Cancer Biology, U3 Pharma GmbH, Martinsried 82152, Germany.
authors: Reimar
authors: R
authors: Abraham
authors: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Alfred L
authors: 0000000283195856
authors: AL
authors: Goldberg
authors: Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
authors: Bert
authors: B
authors: Blaauw
authors: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Ronald A
authors: RA
authors: DePinho
authors: 1] Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy [2] Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy [3] Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35129 Padova, Italy [4] Department of Medicine, McGill University, Montreal, Quebec H3AoG4, Canada [5] Dulbecco Telethon Institute at Telethon Institute of Genetics and Medicine (TIGEM), 80131 Napoli, Italy.
authors: Marco
authors: M
authors: Sandri
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D018797:Cell Cycle Proteins; D004260:DNA Repair; D005260:Female; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D005943:Gluconeogenesis / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; C467200:Foxo1 protein, mouse; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex