Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology

Abstract

The Beclin family, including yeast Atg6 (autophagy related gene 6), its orthologs in higher eukaryotic species, and the more recently characterized mammalian-specific Beclin 2, are essential molecules in autophagy and other membrane-trafficking events. Extensive studies of Beclin orthologs have provided considerable insights into the regulation of autophagy, the diverse roles of autophagy in physiology and disease, and potential new strategies to modulate autophagy in a variety of clinical diseases. In this review we discuss the functions of Beclin orthologs, the regulation of such functions by diverse cellular signaling pathways, and the effects of such regulation on downstream cellular processes including tumor suppression and metabolism. These findings suggest that Beclin orthologs serve as crucial molecules that integrate diverse environmental signals with membrane trafficking events to ensure optimal responses of the cell to stressful stimuli.

Keywords: LC3-associated phagocytosis; autophagic maturation; autophagy; endocytic maturation; endolysosomal trafficking.

Figure 1

Model of mammalian Beclin 1 class III phosphatidylinositol 3-kinase (PI3K) complexes. Beclin 1 homodimerization (top) favors binding to Bcl-2 and disfavors binding to the Vps34-containing class III PI3K complex. Beclin 1 monomers form distinct class III PI3K complexes (often referred to as PI3KC3-C1 and PI3KC3-C2), including an autophagy-active complex containing Atg14, Vps15, Vps34, and NRBF2 (left) as well as a complex that functions in endocytic trafficking containing UVRAG, Bif1, Vps15, and Vps34 (middle). The Beclin 1-containing class III PI3K complex (PI3KC3-C2) that functions in endocytic trafficking is inhibited by Rubicon, which also preferentially binds to Beclin 1 dimers, not shown here (right). The complete structure of these complexes has not been solved, and therefore the precise spatial arrangement of proteins in these complexes is not yet known.

Figure 2

Functions of Atg6/Beclin 1 and Beclin 2 in diverse membrane trafficking processes. Yeast Atg6 and mammalian Beclin 1 function in autophagy and vacuolar protein sorting, and mammalian Beclin 1 functions in LC3-associated phagocytosis. The mammalian-specific protein Beclin 2 functions in autophagy, and in a class III PI3K-independent manner, in GPCR endolysosomal trafficking. The autophagy protein names are shown as yeast or mouse; similar functions exist for the human orthologs. Abbreviations: ER, endoplasmic reticulum; GPCR, G protein-coupled receptor; LC3, microtubule-associated protein 1 light chain 3; PE, phosphatidylethanolamine; PI3K, phosphatidylinositol 3-kinase.

Figure 3

Mechanisms of regulation of Beclin 1 function. The autophagy activity of Beclin 1 is regulated by several kinases that phosphorylate (P) Beclin 1 (top left box), by ubiquitination modifications (top right box), by post-translational modifications or protein–protein interactions that sequester Beclin 1 in the cytoskeleton (left middle box) or Golgi (left middle right box), by post-translation modifications that promote Beclin 1–Rubicon interaction at the endosome (left middle right box), and by several mechanisms that regulate the interaction between Bcl-2/Bcl-X_L and Beclin 1 at the endoplasmic reticulum (lower box).