Macroautophagy is an intracellular catabolic mechanism mediating the turnover of cytoplasmic constituents including large protein complexes and organelles. Autophagy plays an important role in regulating cellular homeostasis and contributes to cell survival, growth, differentiation and host defense responses. Autophagy is also responsible for cellular self-purification, through the degradation and recycling of old proteins and intracellular organelles to maintain environmental stability and intracellular metabolic balance. Recent studies have demonstrated the evolutionary conservation of the core autophagy genes from yeast to mammal; however, the mechanism and regulation of mammalian autophagy have shown significant increases in the complexity which we still know very little. Furthermore, most of the studies on the regulation of autophagy have focused on the activation of autophagy during starvation conditions. We know very little about how autophagy is regulated under normal nutritional conditions.Small molecules have become very important tools for characterizing biological mechanisms in cell biology. There is an urgent need for specific and potent small molecule regulators of autophagy.

　　 Recently, scientists from Shanghai institute of Organic Chemistry, Chinese Academy of Sciences and Harvard Midical School have identified a new autophagy inhibitor, named "spautin" for Specific and Potent Autophagy Inhibitor. Spautin inhibits autophagy with IC50 of 0.89 uM, which is ~10,000 more potent than 3-MA, the commonly used autophagy inhibitor in many published papers. The researchers found that this inhibitor promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two de-ubiquination enzymes, USP10 and USP13, that target the Beclin 1 subunit of Vps34 complexes. Beclin 1 is a tumor suppressor and frequently momoallelically lost in human cancers. Interestingly, Beclin 1 also controls the protein stabilities of USP10 and USP13 by regulating their de-ubiquinationactivities. Since USP10 also mediates the deubiquitination of p53, regulating the stability of USP10 and USP13 by Beclin 1 provides a mechanism for Beclin 1, their studies provide a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1.

　　 This work was done through the collaboration between Prof. Dawei Ma`s group and Prof. Junying Yuan`s group, and was published in Cell (2011, 147, 223).