Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy.
Giulia MilanVanina RomanelloFrancesca PescatoreAndrea ArmaniJi-Hye PaikLaura FrassonAnke SeydelJinghui ZhaoReimar AbrahamAlfred L GoldbergBert BlaauwRonald A DePinhoMarco SandriPublished in: Nature communications (2015)
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.
Keyphrases
- transcription factor
- signaling pathway
- skeletal muscle
- dna repair
- cell death
- amino acid
- dna damage
- endoplasmic reticulum stress
- small molecule
- cell proliferation
- genome wide identification
- dna binding
- pi k akt
- oxidative stress
- binding protein
- gene expression
- heavy metals
- young adults
- squamous cell carcinoma
- dna methylation
- papillary thyroid
- risk assessment
- protein protein
- network analysis
- bioinformatics analysis