Figure 8. Model illustrating a role for Foxk1 repression of autophagy and atrophy induction.

(a) Autophagy genes are transcriptionally repressed through the direct binding of Foxk proteins and recruitment of Sin3A-HDAC complexes, resulting in the reduction of activating H4ac marks. Gene repression exerted through Foxk proteins is controlled downstream of mTOR complex 1 (mTORC1) activity, as mTORC1 inhibition, either through rapamycin or starvation treatment, prevents nuclear import of Foxk1. These observations suggest that mTORC1 negatively regulates autophagy by (1) inhibiting the activation of autophagy-initiating Ulk1 complexes^47,48 and (2) promoting the nuclear import and transcriptional repression of Foxk targets, including components of the Ulk1 and Vps34 complexes. mTORC1 thus effectively down-regulates autophagy through non-transcriptional and transcriptional means. (b) Starvation leads to the inhibition of the Akt-mTORC1-Foxk1 axis. Inhibition of mTORC1 prevents nuclear import of the Foxk proteins and, hence, leads to de-repression of autophagy and atrophy genes, mirroring depletion of Foxk. In addition, Akt inhibition permits nuclear import and subsequent binding of Foxo3 at the promoters of these same genes, leading to the upregulation of their expression.