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. 2010 Apr;22(2):140-9.
doi: 10.1016/j.ceb.2010.01.001. Epub 2010 Jan 22.

The Beclin 1 interactome

Congcong He  1 , Beth Levine
Affiliations

The Beclin 1 interactome

Congcong He et al. Curr Opin Cell Biol. 2010 Apr.

Abstract

The mammalian ortholog of yeast Atg6/Vps30, Beclin 1, is an essential autophagy protein that has been linked to diverse biological processes, including immunity, development, tumor suppression, lifespan extension, and protection against certain cardiac and neurodegenerative diseases. In recent years, major advances have been made in identifying components of functionally distinct Beclin 1/class III phosphatidylinositol 3-kinase complexes, in characterizing the molecular regulation of interactions between Beclin 1 and the autophagy inhibitors, Bcl-2/BcL-X(L), and in uncovering a role for viral antagonists of Beclin 1 in viral pathogenesis. The rapidly growing list of components of the 'Beclin 1 interactome' supports a model in which autophagy, and potentially other membrane trafficking functions of Beclin 1, are governed by differential interactions with different binding partners in different physiological or pathophysiological contexts VSports手机版. .

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Figures

Figure 1
Figure 1
Function of proteins that interact with Beclin 1/class III PI3K complexes in different steps of autophagy. Beclin 1, Vps34, Vps15, and possibly Ambra 1, compose a class III PI3K core complex that binds either Atg14 or UVRAG. Atg14 activates the core complex and biogenesis of autophagosomes; however, there are conflicting reports as to whether UVRAG/Bif-1 facilitates the core complex and upregulates autophagosome formation. A better studied function of UVRAG is promoting the maturation of autophagosomes and endocytic vesicles by recruiting class C Vps and the Rab7 GTPase and inducing vesicle fusion. As an important negative regulator of autophagy, Rubicon inhibits multiple steps in autophagy, including the formation of autophagosomes and the fusion between lysosomes and autophagosomes/endocytic vesicles. However, it is not yet known whether Rubicon inhibits autophagosome formation directly through an inhibitory interaction with the core complex or whether Beclin 1 is involved in the inhibitory effects of Rubicon on autophagosome/endosome maturation. Green arrows, stimulatory action; red bars, inhibitory action.
Figure 2
Figure 2
Mechanisms underlying the regulation of Bcl-2/Bcl-XL interactions with Beclin 1. (a) When Bcl-2/Bcl-XL are bound to Beclin 1, they inhibit autophagy. The disruption of Bcl-2/Bcl-XL–Beclin 1 interactions is essential for autophagy activation. Mechanisms by which this occurs include post-translational modifications of either Bcl-2/Bcl-XL or Beclin 1 (b); competitive disruption of Bcl-2/Bcl-XL binding to Beclin 1 by BH3-only proteins (e.g. Bad, EGL-1) or BH3 mimetics (e.g. ABT737) (c), or potentially, effects of membrane-anchored receptors or their adaptors on Bcl-2/Beclin 1 interactions (d). In (b), starvation induces JNK1-dependent phosphorylation of residues T69, S70, and S87 of Bcl-2, resulting in the disruption of Bcl-2 from Beclin 1. The death-associated kinase, DAPk, phosphorylates residue T119 in the BH3 domain of Beclin 1, leading to the disruption of Bcl-2 from Beclin 1. In (d), Beclin 1 is released from ER-localized inositol-1,4,5-trisphosphate receptor (IP3R) and Bcl-2 after antagonist binding or during starvation, leading to activation of autophagy. The activation of Toll-like receptors recruits the adaptor proteins MyD88 and TRIF, which interact with Beclin 1 and decrease the inhibitory interaction of Bcl-2 with Beclin 1. Green arrows, autophagy induction; red bars, autophagy inhibition.
Figure 3
Figure 3
The Beclin 1 viral protein interactome and their presumed sites of anti-autophagy action. HSV-1 ICP34.5 and γ-herpesvirus-encoded viral Bcl-2 molecules inhibit autophagosome formation through their interactions with Beclin 1, whereas HIV-1 Nef and influenza M2 block the maturation step of autophagy. The anti-autophagic maturation activity of HIV-1 Nef is thought to be mediated by interactions with Beclin 1 (see text), whereas it is not yet known whether the anti-autophagic maturation activity of influenza M2 is mediated by its interaction with Beclin 1.
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References

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