Autophagic flux regulation by the cholesterol/H+ antiporter PTCH1

点击翻译按钮获取中文摘要

Development of a fertilized egg into a properly formed embryo requires a number of signals that perfectly orchestrate the formation of tissues and organs. One of those important signalling events is the so-called "Hedgehog" pathway that when absent provokes very serious congenital defects incompatible with life. Conversely, excessive activity of the Hedgehog pathway after birth is a common cause of childhood brain tumours and adult brain, skin, lung, prostate, and gut cancers. My group has contributed to the understanding of how the Hedgehog signals are perceived by cells and transmitted into different outcomes, depending on the tissue type and the context. Here, we propose to investigate a novel function of the Hedgehog pathway in regulating autophagy, the "self-eating" behaviour of cells. We found that the Hedgehog receptor PTCH1, a tumour suppressor, inhibits autophagy. Cells normally feed themselves from available nutrients; however, in conditions of starvation like those encountered by tumour cells that grow faster that the vasculature that nourishes them, cells degrade part of their contents to survive. Autophagy is essential for cancer cells survival. We will investigate how the Hedgehog pathway regulates autophagy at the molecular level. We will build onto our recent publication that shows that interaction between the C-terminal domain of PTCH1 and ATG101 is necessary for inhibition of autophagy, characterised by reduced number of acidic vesicles where degradation occurs. We propose that PTCH1 acts as a transporter, dissipating the proton gradient of those vesicles (autolysosomes) by a mechanism coupled to cholesterol transport. We will test this hypothesis and will investigate if this function of PTCH1 is lost by mutations of the C-terminal domain frequently found in cancer. We hope that our findings will increase the knowledge on new targets for cancer therapy and will reveal new ways in which cells adapt and survive to different stressors.