Small molecule “on” and “off” switches for autophagy

Abstract

Autophagy, a lysosome‐dependent catabolic process involved in the turnover of cellular components, mediates normal homeostasis during development and protects multicellular eukaryotes from neurodegeneration, cancer and other diseases. However, the mechanisms regulating autophagy under normal nutritional conditions most frequently encountered by cells in organisms under physiological conditions remain unknown. During the past four years, we have used small molecules as tools to explore the regulatory mechanisms that lead to both activation (“on”) and inhibition (“off”) of autophagy in mammalian cells. We have discovered a molecular mechanism for small molecules which can act as an “on” switch for activating autophagy by regulating intracellular Ca2+ current and calpain1 regulated ATG5 cleavage under normal nutritional conditions. Furthermore, we have explored the targeting mechanism of spautin‐1, a small molecule “off” switch for autophagy, and discovered a novel protein deubiquitination mechanism that regulates the turnover of Vps34 complexes, the class III PI3 kinase that plays an essential role in mediating autophagy. Using spautin‐1 as a tool, we elucidated an unexpected connection beclin1, the class III PI3 kinase and tumor suppressor p53, providing an important molecular mechanism that directly links autophagy with tumor suppression.