Regulation of Foxo-dependent transcription by post-translational modifications

Abstract

The Forkhead Box O (Foxo) proteins represent an evolutionarily conserved family of transcription factors that play an important role in regulating processes including metabolism, longevity, and cell death/survival. How is it that a single transcription factor can initiate such divergent cellular responses? We will review the evidence that specific patterns of post-translational modifications play a key role in directing Foxo into various transcriptional readouts. This regulation appears to take on a two tiered regulatory model; with a group of well defined post-translational modifications regulating nuclear localization and transcriptional activity while a second set of modifications regulate the transcriptional specificity of Foxo.

Fig. (1)

Numerous residues on Foxo are regulated via phosphorylation. These sites influence Foxo’s subcellular localization, transcriptional potency and specify gene targets for activation. *This SGK site is not present in Foxo6. **This JNK site is only present in Foxo4.

Fig. (2)

The acetylases CBP and p300 play an important role in chromatin remodeling, allowing Foxo to effectively transcribe its targets. Interestingly CBP/p300 also have an inhibitory effect on Foxo DNA binding through acetylation of the Foxo DNA binding domain. This negative regulatory effect is counteracted by the histone deaeetylases SIRTl and SIRT2. Foxo acetylation can also potentially be prevented through monoubiquitination of the lysines in Foxo’s DNA bidning domain. Monoubiquitinaiton also primes Foxo for potential polyubiquitination and eventual degradation.