Role of HSF1 and FoxO3 in proteotoxic stress induced Macroautophagy

Abstract

Autophagy or Macroautophagy and the ubiquitin‐proteasome pathways are the two major catabolic pathways in all cells. Autophagy is a cellular process in which a portion of the cytoplasm becomes enclosed in a membrane‐bound vesicle, the autophagosome, which fuses with lysosomes leading to digestion of the contents of this autolysosomes. The exact mechanism is still not clear. Autophagy appears to switch on when translation is switched off and the processes are reciprocally regulated by TORC1 kinase. In addition to induction of autophagy by nutrient starvation, this process is also triggered by various stresses. Thus, this process of autophagy is regulated by two different mechanisms: nontranscriptional inhibition by mTOR and transcription‐dependent upregulation through FoxO3. Nevertheless, transcriptional mechanisms that physiologically regulate expression of autophagy genes in tissues other than myotubes have not been characterized. We are concentrated here on autophagy stimulated by proteotoxic stresses such as heat shock. We found that FoxO3 transcription factor which is necessary and sufficient for induction of autophagy in skeletal muscle is regulated by the heat shock protein transcription factor, HSF1. Our data show that HSF1 negatively regulates FoxO3 activity in HeLa cells. FoxO3 is shown to be positively regulating autophagosome formation determined by LC3I/II expression. In this study we hypothesize that stress enhances autophagy by activating FoxO3 and MAP‐LC3I expression whereas stress induced HSF1 activation causes increase in protein folding pathway.