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.

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis, but their role in longevity still remains to be elucidated. FOXO proteins function mainly as transcriptional activators by binding the consensus core recognition motif TTGTTTAC, and their activity is inhibited by the IIS pathway (Biggs et al ., 1999; Brunet et al ., 1999; Henderson & Johnson, 2001; Lin et al ., 2001; Calnan & Brunet, 2008; Zanella et al ., 2010; Webb & Brunet, 2014). Briefly, insulin or IGF‐1 triggers an intracellular pathway mediated by PI3K‐AKT, allowing phosphorylation of FOXO factors by the serine/threonine kinase AKT at three conserved residues within the FOXO proteins.…”

“…Conversely, in the absence of growth factor signaling or upon cellular stress, FOXOs translocate into the nucleus and activate FOXO‐dependent gene expression. A diverse set of posttranslational modifications in addition to phosphorylation, such as acetylation/deacetylation, methylation, or ubiquitination has been shown to promote changes of subcellular localization, protein levels, DNA binding, and transcriptional activity of FOXO factors (Calnan & Brunet, 2008; Webb & Brunet, 2014) The combinatorial result of FOXO posttranslational modifications has been proposed to lead to the recruitment of specific FOXO‐binding partners regulating different FOXO‐dependent gene expression programs (Greer et al ., 2007b; Calnan & Brunet, 2008; Hill et al ., 2014). Several mechanisms of how FOXO proteins promote longevity have been suggested.…”

“…Webb & Brunet (2014) have recently unveiled the role of FOXOs as prolongevity factors through the maintenance of protein homeostasis (proteostasis) (Morley et al ., 2002; Hsu et al ., 2003). In fact, it has been shown that FOXO factors participate in the regulation of genes responsible for two main mechanisms of intracellular clearance: autophagy and the ubiquitin‐proteasome system (Webb & Brunet, 2014).…”

“…In fact, it has been shown that FOXO factors participate in the regulation of genes responsible for two main mechanisms of intracellular clearance: autophagy and the ubiquitin‐proteasome system (Webb & Brunet, 2014). Defects in autophagy, the process of degradation and recycling of cytoplasmic proteins and organelles in response to starvation have been associated with premature aging and age‐related disorders (Hara et al ., 2006; Komatsu et al ., 2006; Jung et al ., 2008; Pickford et al ., 2008; Masiero et al ., 2009; Lee et al ., 2010a, 2010b).…”

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

“…The possibility that Tor activation during aging might be partly responsible for the accumulation of these damaged macromolecules has led to the suggestion that rapamycin administration might be helpful in reversing this accumulation. In addition, Foxo plays a critical role in inducing expression of components of the proteasome as well as components of the autophagosome (Webb & Brunet, 2014). Thus, loss of Foxo activity during aging is likely to contribute to loss of proteostasis through multiple outputs.…”