Cited by 114Muscle Physiology and DisordersFOXO transcription factor regulationAmyotrophic Lateral Sclerosis Research

Posttranslational modifications control FoxO3 activity during denervation

Open access
Bertaggia, Enrico, Coletto, Luisa, Sandri, Marco·2012·American Journal of Physiology-Cell Physiology

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.

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Registry

Crossref · 10.1152/ajpcell.00142.2011

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  • p300/CBP-mediated acetylation inhibits the FoxO3-dependent atrophy program, while HDAC-mediated deacetylation activates FoxOs.

    “For instance, p300/CBP-mediated acetylation inhibits FoxO3-dependent atrophy program, while HDAC-mediated deacetylation activates FoxOs65,66.”

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Authors
Bertaggia, E., Coletto, L., & Sandri, M.
Affiliations
  • University of Padua (IT)
  • Veneto Institute of Molecular Medicine (IT)
Corresponding author
Sandri, Marco
Venue
American Journal of Physiology-Cell Physiology
Published
2012-02
Volume
302
Issue
3
Pages
C587-C596
ISSN
  • 0363-6143 (ISSN-L)
  • 1522-1563
OpenAlex
W2054800877
Cited by
114
References
36
Citations by year
2026: 2 · 2025: 6 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 10 · 2018: 11 · 2017: 11 · 2016: 10 · 2015: 9 · 2014: 13 · 2013: 6 · 2012: 4
FWCI
2.98
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • American Journal of Physiology-Cell Physiology (publishedVersion)
  • PubMed (publishedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
FOXO3, lysine acetylation, muscle atrophy, denervation, atrogin-1, P300, ubiquitination, proteasomal degradation, cachexia, ubiquitin-proteasome system, autophagy-lysosome system, transcriptional regulation
MeSH terms
Forkhead Box Protein O3, p300-CBP-Associated Factor, Acetylation, Animals, Cells, Cultured, Cytosol, Female, Lysine, Mice, Inbred C57BL, Muscle Denervation, Muscle Proteins, Muscular Atrophy, Mutation, Protein Processing, Post-Translational, Signal Transduction, Transcriptional Activation, Gene Expression, Muscle, Skeletal, RNA Interference, SKP Cullin F-Box Protein Ligases, Proteasome Endopeptidase Complex, p300-CBP Transcription Factors, Mice, Proto-Oncogene Proteins c-mdm2, Forkhead Transcription Factors, Ubiquitination

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