FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response

Abstract

Cellular stress response is a universal mechanism that ensures the survival or negative selection of cells in challenging conditions. The transcription factor Forkhead box protein O3 (FOXO3a) is a core regulator of cellular homeostasis, stress response, and longevity since it can modulate a variety of stress responses upon nutrient shortage, oxidative stress, hypoxia, heat shock, and DNA damage. FOXO3a activity is regulated by post-translational modifications that drive its shuttling between different cellular compartments, thereby determining its inactivation (cytoplasm) or activation (nucleus and mitochondria). Depending on the stress stimulus and subcellular context, activated FOXO3a can induce specific sets of nuclear genes, including cell cycle inhibitors, pro-apoptotic genes, reactive oxygen species (ROS) scavengers, autophagy effectors, gluconeogenic enzymes, and others. On the other hand, upon glucose restriction, 5'-AMP-activated protein kinase (AMPK) and mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -dependent FOXO3a mitochondrial translocation allows the transcription of oxidative phosphorylation (OXPHOS) genes, restoring cellular ATP levels, while in cancer cells, mitochondrial FOXO3a mediates survival upon genotoxic stress induced by chemotherapy. Interestingly, these target genes and their related pathways are diverse and sometimes antagonistic, suggesting that FOXO3a is an adaptable player in the dynamic homeostasis of normal and stressed cells. In this review, we describe the multiple roles of FOXO3a in cellular stress response, with a focus on both its nuclear and mitochondrial functions.

Keywords: FOXO3a; cellular homeostasis; nuclear/mitochondrial crosstalk; stress response; transcription factors.

Figure 1

Post-translational regulation of FOXO3a. (A) Schematic representation of FOXO3a domains (MPP-MIP motifs, consensus motifs for mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP); forkhead domain, FH; nuclear localization signal, NLS, Kinase-inducible domain interacting domain binding domain, KIX; transactivation domain TAD). (B) Summary of FOXO3a post-translational modifications (PTMs). Depicted are the most important upstream signals (AKT8 virus oncogene cellular homolog, AKT; serum and glucocorticoid-induced kinase, SGK;5′-AMP-activated protein kinase AMPK; c-Jun N-terminal kinase, JNK; extracellular signal-regulated kinase, ERK, SET domain protein 9, SET9) regulating FOXO3a subcellular localization and activity through reversible PTMs, which include phosphorylation (blue circle) and methylation (green circle) on specific amino acid residues (T, threonine; S, serine; K, methionine).

Figure 2

Schematic representation of Forkhead box O3 (FOXO3a)-mediated stress response. Perturbations of cellular homeostasis, such as nutrient shortage, high concentration of intracellular ROS, or genotoxic stress, activate FOXO3a upstream stress sensors (purple boxes), which in turn modulate FOXO3a subcellular localization and/or activity through various post-translational modifications (PTMs) (green arrows represent activation signals, red bar-headed lines represent inhibitory effects). In the cytoplasm, FOXO3a is inactive and is targeted for poly-ubiquitination, which leads to its further proteasomal degradation. Upon phosphorylation by c-Jun N-terminal kinase (JNK), FOXO3a is shuttled into the nucleus, where its transcriptional activity is further regulated by an activator (e.g., 5′-AMP-activated protein kinase, AMPK; sirtuin 1, SIRT1) or repressor (e.g., AKT8 virus oncogene cellular homolog AKT, CREB binding protein and p300 (CBP/p300) signals. Depending on the PTM pattern, FOXO3a orchestrates different transcriptional programs involved in several cellular processes, including apoptosis, cell cycle progression, DNA repair, reactive oxygen species (ROS) detoxification, and cellular metabolism. Recent evidence showed that metabolic stress or chemotherapy treatment can also promote AMPK- and extracellular signal-regulated kinase (ERK) dependent mitochondrial accumulation of a FOXO3a cleaved form, which activates the expression of mitochondrial oxidative phosphorylation (OXPHOS) genes involved in cell survival. The crosstalk between FOXO3a nuclear and mitochondrial functions is crucial for the restoration and maintenance of cellular homeostasis.