Editors' ChoiceAUTOPHAGY

Always at Your Beclin Call

Sci. Signal.  10 Sep 2013:
Vol. 6, Issue 292, pp. ec214
DOI: 10.1126/scisignal.2004708

Autophagy is a process by which cells engulf unused or dysfunctional cellular components and is stimulated by nutrient deprivation or other forms of stress. Autophagosomes fuse with lysosomes, and their contents can be recycled as building blocks for new proteins and organelles. Several autophagy-related genes have been characterized in species from yeast to humans, including Beclin 1. He et al. identified the autophagy-related gene Beclin 2 and found that it was required not only for autophagy but also for the lysosomal degradation of G protein–coupled receptors (GPCRs). He et al. identified Beclin 2 on the basis of its homology to Beclin 1. Like Beclin 1, Beclin 2 bound to several other autophagy-associated proteins and was required for the degradation of sequestrosome 1 (also known as p62) and the lipidation and accumulation of the microtubule-associated protein LC3 into autophagosomes in response to nutrient deprivation. siRNA-resistant mRNA encoding Beclin 2 rescued the defects in autophagy resulting from knockdown of Beclin 2 but not from that of Beclin 1, suggesting that these two proteins were not functionally redundant. A yeast two-hybrid screen with the N terminus of Beclin 2, which shows less conservation to Beclin 1, identified GASP1 (GPCR-associated sorting protein 1). Coimmunoprecipitation of GASP1 from human or mouse cells confirmed selectivity for Beclin 2 and not Beclin 1. GASP1 is required for ligand-induced lysosomal degradation of GPCRs, and knockdown of Beclin 2 prevented internalization and degradation of several GPCRs. Overexpression of siRNA-resistant wild-type Beclin 2, but not an I80S mutant of Beclin 2 that failed to bind GASP1, rescued GPCR internalization and degradation in the Beclin 2–knockdown cells. The I80S Beclin 2 mutant restored autophagy in Beclin 2–knockdown cells, consistent with the fact that GASP1 is not required for autophagy and suggesting distinct mechanisms for the roles of Beclin-2 in autophagy and GPCR degradation. Cells from mice with a biallelic deletion of beclin 2 showed reduced amounts of basal and starvation-induced autophagy, although not to the same severity as those from mice with monoallelic deletion of beclin 1. In contrast, the brains of beclin 2+/– mice showed increased abundance of the cannabinoid receptor 1 (CB1R), a GPCR regulated by GASP1, whereas the brains of beclin 1+/– mice did not. Hyperactivation of CB1R in mice promotes overconsumption of food, leading to weight gain and diabetes. Likewise, beclin 2+/–mice fed a high-fat diet developed similar symptoms, including decreased glucose tolerance and insulin sensitivity, when compared with wild-type mice on the same diet. Homologs of Beclin 2 were not found in nonmammalian vertebrates. Given that Beclin 1 does not play a role in GPCR homeostasis, this implies that coordinate regulation of autophagy and GPCR turnover is an evolutionarily new function for the Beclin protein family. Together, these findings show that Beclin 2 has distinct functions in two lysosomal-mediated degradation processes, autophagy and GPCR degradation.

C. He, Y. Wei, K. Sun, B. Li, X. Dong, Z. Zou, Y. Liu, L. N. Kinch, S. Khan, S. Sinha, R. J. Xavier, N. V. Grishin, G. Xiao, E.-L. Eskelinen, P. E. Scherer, J. L. Whistler, B. Levine, Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell 154, 1085–1099 (2013). [Pubmed]