title: Posttranslational modifications control FoxO3 activity during denervation.
abstract: Loss of muscle mass occurs in a variety of diseases including cancer, chronic heart failure, AIDS, diabetes, and renal failure, often aggravating pathological progression. The atrophy process is controlled by a transcriptional program that regulates the expression of a subset of genes named atrophy-related genes. The Forkhead Box O (FoxO) family of transcription factors plays a critical role in the atrophy program being sufficient and necessary for the expression of rate-limiting enzymes of ubiquitin-proteasome and autophagy-lysosome systems. Therefore, a fine regulation of FoxOs is critical to avoid excessive proteolysis and cachexia. FoxO activity can be modulated by different mechanisms including phosphorylation, acetylation, ubiquitination, and glycosylation. Here we show that FoxO3 is progressively acetylated during denervation and concomitantly atrogin-1, the bona fide FoxO3 target, is downregulated. FoxO3 interacts with the histone acetyl-transferase p300, and its acetylation causes cytosolic relocalization and degradation. Several lysine residues of FoxOs are known to be acetylated. To identify which lysines are critical for FoxO3 activity we have generated different FoxO3 mutants that either mimic or prevent lysine acetylation. We found that FoxO3 mutants that mimic acetylation show a decrease of transcriptional activity and cytosolic localization. Importantly, acetylation induces FoxO3 degradation via proteasome system. Between the different lysines, lysine 262 is critical for translocation of FoxO3. In conclusion, we provide evidence that FoxO3 activity is negatively modulated by acetylation and ubiquitination in a time-dependent and coordinated manner. This fine-tuning mechanism of FoxO3 regulation may be important to prevent excessive muscle loss and can be used as a therapeutic approach to counteract muscle wasting.
authors.affiliation: Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertaggia
authors.forename: Luisa
authors.initials: L
authors.lastname: Coletto
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D003600:Cytosol; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009121:Muscle Denervation; D009124:Muscle Proteins / Q000096:biosynthesis; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis; D015398:Signal Transduction; D015533:Transcriptional Activation; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008239:Lysine; D009124:Muscle Proteins; D046988:Proteasome Endopeptidase Complex; D051736:Proto-Oncogene Proteins c-mdm2; D044843:SKP Cullin F-Box Protein Ligases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C474033:FoxO3 protein, mouse; C486691:Fbxo32 protein, mouse; C497207:Mdm2 protein, mouse