Trends in Cell Biology
ReviewThe Beclin 1–VPS34 complex – at the crossroads of autophagy and beyond
Introduction
Autophagy is a catabolic pathway used to break down and recycle long-lived proteins and injured organelles (Box 1). At least thirty-three AuTophaGy-related (ATG) genes have been found so far in yeast 1, 2, and homologs of many of these genes have been described in higher eukaryotes. The total group of ATG genes can be broken down into functional categories that follow the autophagic processes of induction, vesicle nucleation, vesicle expansion and completion, and recycling, as well as cargo packaging that is specific to selective autophagic degradation of modified proteins or damaged organelles [3]. One of the most-studied mammalian autophagy proteins that falls into the category of vesicle nucleation is Beclin 1 (from ‘Bcl-2-interacting protein’), a 60 kDa coiled-coil protein that contains a Bcl-2-homology-3 (BH3) domain, a central coiled-coil domain (CCD), and an evolutionarily conserved domain (ECD). A function of Beclin 1 in autophagy was first suspected due to its 24.4% amino-acid sequence identity to the yeast autophagy protein Atg6. Beclin 1 was found to restore autophagic activity in Atg6-disrupted yeast, becoming one of the first identified mammalian genes to positively regulate autophagy [4]. Interestingly, Beclin 1 was originally discovered not as an autophagy protein but rather as an interaction partner for the anti-apoptotic protein Bcl-2 [5]. Subsequent studies demonstrated that Beclin 1 is a haploinsufficient tumor- suppressor gene that is either monoallelically deleted or shows reduced expression in several different cancers 6, 7. Several studies have also found that Beclin 1 is involved in several other biological functions and in human conditions including heart disease, pathogen infection, development, and neurodegeneration [8]. However, the precise mechanism of Beclin 1 in these different physiological processes has yet to be elucidated. Clues to the mechanisms underlying the function of Beclin 1 can be found through its interactions with other proteins. Following the initial finding that Beclin 1 binds to Bcl-2 through its BH3 domain, several other partners have been identified that interact through the CCD and ECD domains of Beclin 1. These interacting partners provide potential insight into Beclin 1's different physiological roles, both in autophagy and in processes independent of autophagy.
Because the autophagic pathway is conserved among eukaryotes, many of the protein–protein interactions and protein complexes found in yeast are also identified in mammals. One primary example is the critical core complex formed from the yeast counterpart to Beclin 1, Atg6, and the class III phosphatidylinositol 3-kinase (PI(3) kinase) Vps34 (Box 2) that plays a role in vesicle nucleation in autophagy and hydrolase sorting through the vacuolar protein sorting (Vps) pathway [9]. The mammalian Beclin 1–VPS34 core autophagy complex resembles the yeast Atg6–Vps34 complex. Several different autophagy complexes consisting of Beclin 1–VPS34 and a selection of binding partners for Beclin 1 have recently been identified in mammalian cells 10, 11, 12, 13, 14, 15. Recent studies suggest a central role for Beclin 1 complexes in controlling human VPS34-mediated vesicle trafficking pathways including autophagy. This review focuses on the newly identified Beclin 1 complexes, the regulation of the autophagic process by these distinct complexes, and discusses the emerging questions that await future investigation before the molecular mechanism of autophagy control can be fully understood.
Section snippets
Multiple autophagy complexes with distinct functions
A central question for understanding the regulation of autophagy is whether the Beclin 1–VPS34 complex has a similar function to its yeast homolog in autophagy and whether it has gained additional functions during evolution. Whereas the yeast Atg6–Vps34 complexes and their functions have been well documented, Beclin 1–VPS34 interactions with different proteins and the resulting changes in autophagic function are just beginning to be elucidated.
Beclin 1–VPS34 core complexes and physiological binding partners in mammals
For some time Beclin 1 has been known to form a protein complex consisting of VPS34 and p150/VPS15 and has been predicted to regulate autophagy in a similar manner to yeast [9]. Whereas the binding of Beclin 1 to VPS34/VPS15 suggests a conserved function of Beclin 1 in autophagy, the association of Beclin 1 with an additional set of proteins implicates Beclin 1 in diverse functions that remain to be defined. These observations raise the question of what proteins constitute the core complex of
Antiapoptotic Bcl-2 family regulation of Beclin 1 complexes and autophagy activity
Previous studies have shown that some antiapoptotic members of the Bcl-2 family (Box 3), such as Bcl-2, Bcl-xL, and viral Bcl-2 homologs vBcl-2 (from Kaposi's sarcoma associated herpes virus and from herpes virus γHV68M11), interact with Beclin 1 5, 28, 29, 30. A series of investigations have shown that antiapoptotic Bcl-2 proteins inhibit the autophagic function of Beclin 1 through binding to its BH3 domain 28, 31, thereby suggesting that Bcl-2 family members also function as inhibitors for
Additional Beclin 1 binding proteins
Other proteins, including Ambra 1, Bif-1, nPIST, inositol 1,4,5-trisphosphate receptor (IP(3)R), and VMP1, have also been previously reported to be Beclin 1-binding proteins 13, 14, 38, 39, 40. Because they were not found in the stable Beclin 1–VPS34 complexes as shown by affinity purification 10, 11, 12, 21, their association with this complex is probably ‘loose’ or transient in nature. In some cases the binding is indirect, as shown for Endophilin B1 (Bif-1) that interacts with Beclin 1
Concluding remarks
Current studies demonstrate pleiotropic functions for Beclin 1–VPS34 complexes in autophagy control and the complexity of the autophagy process. The evidence reveals a core Beclin 1–VPS34–VPS15 complex that can be tightly associated with UVRAG, Atg14L or Rubicon under normal conditions. It remains possible that many other previously known Beclin 1-binding proteins are peripheral to these proteins or function to regulate VPS34 kinase activity through these proteins. Therefore, a centralized
Acknowledgements
We thank members of Yue laboratory and Dr. Qing Zhong for critical reading. This work was supported by NIH grant RO1NS060123 (Z.Y.), Michael J. Fox Foundation for Parkinson's Research (Z.Y.) and NIH COBRE 2P20RR020171 (Q.J.W.). We apologize to colleagues whose publications could not be cited owing to space limit.
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