Beclin 2 Regulates G Protein-Coupled Receptor Degradation and Autophagy

The relationship between autophagy, a process in which intracellular components are lysosomally degraded, and other lysosomal degradation pathways that target extracellular receptors is unclear, though the duplication of autophagy genes in the human genome suggests that specification and diversification of functions have occurred. By performing a sequence alignment search, He and colleagues identified a previously uncharacterized mammalian-specific gene that shared 57% sequence identity with the essential autophagy gene beclin 1, which they named beclin 2. Unlike beclin 1, which has exons and is ubiquitously expressed, beclin 2 is intronless and shows a more restricted expression pattern, raising the possibility that Beclin family members have tissue-specific functions and regulatory mechanisms. Beclin 2 was found to interact with several known Beclin 1-interacting proteins, and like Beclin 1, was required for autophagy in human cells. However, Beclin 2 specifically interacted with G protein-coupled receptor (GPCR)-associated sorting protein 1 (GASP1), which functions in the agonist-induced lysosomal degradation of a subset of GPCRs. Knockdown of Beclin 2, but not Beclin 1, blocked postendosomal sorting of internalized GASP1-regulated GPCRs to the lysosome and allowed their recycling back to the plasma membrane, indicating that Beclin 2 has an autophagy-independent role in regulation of GPCR trafficking. The Beclin 2–GASP1 interaction was dispensable for autophagy, also suggesting that the roles of Beclin 2 in GPCR degradation and autophagy are independent. Consistent with these in vitro findings, beclin 2-null mice had lower embryonic and postnatal survival rates than heterozygous and wild-type mice, and autophagy and GASP1-dependent GPCR degradation were impaired in beclin 2-deficient mouse embryonic fibroblasts. The characterization of Beclin 2 and its dual functions in autophagy and GPCR trafficking add another layer of complexity to the regulation and integration of lysosomal degradation pathways in mammalian cells.

He C, Wei Y, Sun K, Li B, Dong X, Zou Z, et al. Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell 2013 Aug 15 [Epub ahead of print].