(A) FOXO regulates induction of the autophagic pathway (phagophore development) and formation of the autophagosome. Genes regulated by FOXO in various cell types are listed in red. Whether FOXO also regulates genes that promote the fusion, trafficking and maturation of the autolysosome is not yet known. (B) FOXO factors regulate mitophagy via the E3 ubiquitin ligase MUL1 (muscle) and PINK1, which recruits the E3 ubiquitin ligase PARKIN (fibroblasts and MCF-7 cells). Both enzymes tag MFN2 for degradation, which targets mitochondria for mitophagy. (C) FOXOs activate the transcription of ATG14, a protein that localizes to the inner face of the phageophore, to promote lipophagy. FOXO1 can also promote transcription of lipoprotein lipase, an enzyme that promotes triglyceride release, but it not known if this regulation is direct. In all panels, genes highlighted in red have been shown to be FOXO targets.

Under low nutrient conditions, the serine/threonine kinase ULK1 initiates activation of autophagy. Under these conditions, FOXO activates transcription of glutamine synthetase, which increases intracellular glutamine levels, thereby blocking mTOR activity. In C. elegans, and possibly vertebrates, FOXO/DAF-16 represses expression of daf-15/raptor, a critical member of the TORC1 complex. In high nutrient conditions, low FOXO activity relieves the repression of daf-15/raptor. In addition, reduced glutamine synthetase levels increase mTOR activity and autophagy is impeded.

FOXO directly regulates transcription of the E3 ubiquitin ligases Atrogin-1 and Murf1, which target substrates for proteasomal degradation. In hESC, FOXO4 activates transcription of the proteasomal regulatory subunit Psmd11 (rpn-6.1 in C. elegans) thereby maintaining high proteasomal activity in these cells.