FOXO transcription factors: key regulators of cellular quality control

Abstract

FOXO transcription factors are conserved regulators of longevity downstream of insulin signaling. These transcription factors integrate signals emanating from nutrient deprivation and stress stimuli to coordinate programs of genes involved in cellular metabolism and resistance to oxidative stress. Here, we discuss emerging evidence for a pivotal role of FOXO factors in promoting the expression of genes involved in autophagy and the ubiquitin-proteasome system--two cell clearance processes that are essential for maintaining organelle and protein homeostasis (proteostasis). The ability of FOXO to maintain cellular quality control appears to be critical in processes and pathologies where damaged proteins and organelles accumulate, including aging and neurodegenerative diseases.

Keywords: FOXO transcription factors; aging; cellular quality control; proteostasis.

Figure 1. FOXOs regulate the expression of genes involved in autophagy in mammalian cells

(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.

Figure 2. Antagonistic interaction between FOXOs and the mTORC1 pathway in autophagy

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.

Figure 3. FOXOs coordinate the activation of the ubiquitin-proteasome pathway in mammalian cells

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.