Cell 147, 223–234 (2011)

Vsp34, a class III phosphoinositide-3-kinase (PI3K), assembles into multiprotein complexes that include Beclin1 to promote autophagy, a cellular process for the degradation of proteins and organelles. Liu et al. performed an image-based screen followed by extensive structure-activity relationship studies to find spautin-1, a potent inhibitor of autophagy in mammalian cells. Spautin-1 treatment led to reduced amounts of Beclin1 and other components of Vsp34 complexes by promoting the ubiquitination of Beclin1, leading to the hypothesis that spautin-1 inhibits deubiquitinating enzymes (DUBs). To test this, the authors screened siRNAs targeting DUBs; knockdown of USP10 or USP13 resulted in decreased Beclin1 expression and inhibited autophagy. In contrast, overexpression of USP10 or USP13 reduced amounts of ubiquitinated Beclin1. Further investigations revealed that Beclin1 directly interacted with USP13, promoting its DUB activity, and indirectly promoted USP10 activity. In cells treated with spautin-1 and in mice heterozygous for the Beclin1 gene, the authors found that amounts of p53, a known substrate for USP10, were decreased. Together, these data support a model in which class III PI3K components, including Beclin1, regulate p53 levels via direct interaction with DUBs and provide a potential mechanistic explanation for Beclin1's reported tumor-suppressor activity.