The Evolutionarily Conserved Domain of Beclin 1 is Required for Vps34 Binding, Autophagy, and Tumor Suppressor Function

Furuya, Norihiko; Yu, Jack; Byfield, Maya P.; Pattingre, Sophie; Levine, Beth

doi:10.4161/auto.1.1.1542

Cited by 390 publications

(326 citation statements)

References 23 publications

(39 reference statements)

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“…Different binding interactions for the BH3-domain of Beclin-1 bound to Bcl-xL compared with other BH3-domains were also reported (Feng et al, 2007;Oberstein et al, 2007). Moreover, Beclin-1 is bound to many other proteins in addition to Bcl-2 family members (Vps34 (Furuya et al, 2005), UVRAG (Liang et al, 2006;Takahashi et al, 2007), Bif1 (Takahashi et al, 2007) Ambra (Fimia et al, 2007)), which may further obscure the function of the BH3-domain. It is interesting to note that UVRAG was recently reported to modulate the stoichiometry of Beclin-1 binding to Bcl-2/xL (Noble et al, 2008;Samara et al, 2008), but the impact on apoptosis is not known.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

et al. 2009

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The binding of Bcl-2 to Beclin-1 reduces Beclin-1's capacity to induce autophagy. Here, we have tested whether the interaction is reciprocated by loss of Bcl-2's anti-apoptotic function. We targeted Bcl-2 to mitochondria or endoplasmic reticulum (ER) and induced apoptosis using several apoptotic stimuli that initiate ER and/or mitochondrial signaling pathways (UV radiation, TNF and cycloheximide, staurosporine, thapsigargin and tunicamycin). When Beclin-1 and Bcl-2 were expressed together in HeLa cells, Beclin-1 (but not Beclin-1 lacking the Bcl-2-binding domain) followed Bcl-2 to the appropriate organelle with complete or near-complete overlap (comprising 60 and 30% of cells, respectively). The interaction between Beclin-1 and Bcl-2 was verified by immunoprecipitation, and a membrane-proximate localization of Beclin-1 was shown by immunoelectron microscopy. Apoptosis was followed by measuring changes in nuclear morphology, caspase-3 activity, poly-ADP-ribose polymerase cleavage or punctation of mRFP-Bax on mitochondria. Binding of Beclin-1 to Bcl-2 did not modify apoptosis irrespective of Bcl-2 concentration, location or apoptotic stimulus. A similar result was obtained in Atg5À/À cells that are autophagy-deficient, arguing against compensation for the loss of protection by Bcl-2 by autophagy-mediated survival induced by Beclin-1. Hence, although Beclin-1 contains a BH3-only motif typical of pro-apoptotic proteins, it is a negligible modulator of Bcl-2's anti-apoptotic function.

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Section: Discussionmentioning

confidence: 99%

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

et al. 2009

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“…Beclin1 is required for NS-induced autophagy and is an interactive protein of PI3KC3, a putative target of 3-MA. 26 Some endogenous Beclin1 have been localized to the ER. 27 To test the role of Beclin1 in UPR activation, siRNA was used to knock down Beclin1 in HEK293 cells.…”

Section: Resultsmentioning

confidence: 99%

The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells

et al. 2008

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In mammalian cells, endoplasmic reticulum (ER) stress has recently been shown to induce autophagy and the induction requires the unfolded protein response (UPR) signaling pathways. However, little is known whether autophagy regulates UPR pathways and how specific UPR targets might control autophagy. Here, we demonstrated that although ER stress-induced autophagy was suppressed by class III phosphatidylinositol-3 0 -kinase (PI3KC3) inhibitor 3-methyladenine (3-MA), wortmannin and knockdown of Beclin1 using small interfering RNA (siRNA), only 3-MA suppressed UPR activation. We discovered that the UPR regulator and ER chaperone GRP78/BiP is required for stress-induced autophagy. In cells in which GRP78 expression was knocked down by siRNA, despite spontaneous activation of UPR pathways and LC3 conversion, autophagosome formation induced by ER stress as well as by nutrition starvation was inhibited. GRP78 knockdown did not disrupt PI3KC3-Beclin1 association. However, electron microscopic analysis of the intracellular organelle structure reveals that the ER, a putative membrane source for generating autophagosomal double membrane, was massively expanded and disorganized in cells in which GRP78 was knocked down. ER expansion is known to be dependent on the UPR transcription factor XBP-1. Simultaneous knockdown of GRP78 and XBP-1 recovered normal levels of stress-induced autophagosome formation. Thus, these studies uncover 3-MA as an inhibitor of UPR activation and establish GRP78 as a novel obligatory component of autophagy in mammalian cells.

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“…In mammalian cells the Atg1 ortholog ULK1 also controls autophagy (32). Nucleation of the autophagic vesicle involves a Type III PI3 kinase complex that includes the kinase (Vps34) and Beclin1 (Atg6), which interact through a conserved domain in Beclin 1 (33). This complex contains multiple proteins including another putative tumor suppressor called UVRAG (34) and a protein called Ambra1 (35) , which regulate the activity of the kinase and thus control autophagy induction.…”

Section: Regulation Of Autophagymentioning

confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

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Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes. KeywordsAutophagy; Apoptosis; Bcl-2, FADD; Atg 5In the early to mid 1990s there was a rapid increase in our understating about the regulation of apoptosis. Fifteen or so years later we are in the midst of a similarly exciting period for understanding autophagy with very rapid growth of publications on the regulation and function of this process (1). Autophagy (the form of autophagy discussed here is macroautophagy, other forms-microautophagy and chaperone-mediated autophagy share the same lysosomal degradation mechanism but differ in the way that material is delivered to the lysosome) is a degradative process involving sequestration of parts of the cytoplasm in double membrane vesicles (autophagic vesicles or autophagosomes) that fuse with lysosomes forming the autophagolysosome. In the autophagolysosome, the cytoplasmic material that was engulfed is hydrolyzed and the resulting amino acids and other macromolecular precursors can be recycled (2-4), see Fig 1 for a schematic of the process. Autophagy is a mechanism by which organelles are removed and is the primary degradation mechanism for long-lived proteins and thus maintains quality control for proteins and organelles. Autophagy is ubiquitous in eukaryotic cells and important in development and in diverse pathophysiological conditions (5)-for example providing protection against neurodegeneration (6,7), infections (8,9) and tumor development (10-13). Cells that are deficient in autophagy also demonstrate enhanced chromosomal instability (14,15), which may be related to the tumorigenesis associated with autophagy deficiency.Autophagy is important in cell death decisions and can protect cells by preventing them from undergoing apoptosis. For example, increased autophagy in nutrient deprived or growth factorwithdrawn cells allows cell survival (16,17) by inhibiting apoptosis. Autophagy also protects cells from various other apoptotic stimuli (18). It is not clear how autophagy stops cells from undergoing apoptosis; one suggested mechanism is the sequestration of damaged mitochondria (18) thus preventing released cytochrome c from being able to form a functional apoptosome NIH Public Access Autophagic cell death (also known as Type II programmed cell death to distinguish it from apoptosis or Type I programmed cell death) (20-22) has been describ...

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The Evolutionarily Conserved Domain of Beclin 1 is Required for Vps34 Binding, Autophagy, and Tumor Suppressor Function

Cited by 390 publications

References 23 publications

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells

Apoptosis and autophagy: regulatory connections between two supposedly different processes

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