The Beclin 1-VPS34 complex--at the crossroads of autophagy and beyond - PubMed (original) (raw)

Review

The Beclin 1-VPS34 complex--at the crossroads of autophagy and beyond

Sarah F Funderburk et al. Trends Cell Biol. 2010 Jun.

Abstract

An increasing body of research on autophagy provides overwhelming evidence for its connection to diverse biological functions and human diseases. Beclin 1, the first mammalian autophagy protein to be described, appears to act as a nexus point between autophagy, endosomal, and perhaps also cell death pathways. Beclin 1 performs these roles as part of a core complex that contains vacuolar sorting protein 34 (VPS34), a class III phosphatidylinositol-3 kinase. The precise mechanism of Beclin 1-mediated regulation of these cellular functions is unclear, but substantial progress has recently been made in identifying new players and their functions in Beclin 1-VSP34 complexes. Here we review emerging studies that are beginning to unveil the physiological functions of Beclin 1-VPS34 in the central control of autophagic activity and other trafficking events through the formation of distinct Beclin 1-VPS34 protein complexes.

(c) 2010 Elsevier Ltd. All rights reserved.

PubMed Disclaimer

Conflict of interest statement

Note: The authors declare No conflicts of interest.

Figures

Figure 1

Figure 1. Multiple Beclin 1-VPS34 complexes and their distinct functions

(A) An illustration of the multilayered Beclin 1 protein complexes: a core complex Beclin 1-VPS34-VPS15; stable binding partners Atg14L, UVRAG, and Rubicon; unstable or transient binding partners including Bcl-2 homologs, Bif-1, Ambra 1, VMP1, nPIST, Rab5, ICP 34.5, and inositol 1,4,5-triphosphate receptor (IP3R). Among the unstable binding partners, Bif-1 interacts with UVRAG, and IP3R interacts with Bcl-2. (B) In yeast two Atg6-Vps34 complexes, I and II, regulate autophagy and vacuolar protein sorting, respectively. In mammals, multiple Beclin 1 complexes act in different stages of autophagy and perhaps also endocytic trafficking. Atg14L associates with the core Beclin 1-VPS34-VPS15 complex to function in the biosynthesis of autophagosomes, and UVRAG potentially associates with the same core complex to also influence autophagosome formation. However, UVRAG has an additional role in autophagosome maturation in a complex with C-Vps and the Rab7 GTPase that is independent of Beclin 1. Rubicon inhibits autophagosome maturation in a possibly Beclin 1-independent manner. Rubicon could sequester Rab proteins such as Rab 7 through its RUN domain to inhibit this stage of autophagy. The binding of Rubicon to the Beclin 1 core complex though UVRAG may aid in neutralizing such a negative function.

Figure 2

Figure 2. Dynamic regulation of Beclin 1-VPS34 complex formation and autophagy by Bcl-2 family members and Beclin 1 dimerization

Beclin 1-VPS34-VPS15 forms pro-autophagic complexes with Atg14L or UVRAG. Binding of Bcl-2 and Beclin 1 is known to inhibit autophagy by possibly disrupting VPS34 binding; but Bcl-2 binding may also displace other stable interacting partners such as Atg14L (or UVRAG), resulting in autophagy inhibition. Additionally, the anti-autophagic binding of Bcl-2 promotes Beclin 1 homodimerization, which prevents heterodimerization with Atg14L or UVRAG.

Similar articles

Cited by

References

    1. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93. - PMC - PubMed
    1. Kawamata T, et al. Organization of the pre-autophagosomal structure responsible for autophagosome formation. Mol Biol Cell. 2008;19:2039–2050. - PMC - PubMed
    1. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004;6:463–477. - PubMed
    1. Liang XH, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–676. - PubMed
    1. Liang XH, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998;72:8586–8596. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources