Bcl-2 Antiapoptotic Proteins Inhibit Beclin 1-Dependent Autophagy

Pattingre, Sophie; Tassa, Amina; Qu, Xueping; Garuti, Rita; Liang, Xiao; Mizushima, Noboru; Packer, Milton; Schneider, Michael; Levine, Beth

doi:10.1016/j.cell.2005.07.002

Cited by 3,227 publications

(3,168 citation statements)

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“…Although a reduction in levels of Bcl‐2 and Bcl‐XL may suggest an activation of autophagy initiation (Pattingre et al ., 2005), the simultaneous reduction in levels of P27 in addition to Bcl‐2 and Bcl‐XL indicates an impaired autophagy flux (Liang et al ., 2007). MAP1S enhances autophagy initiation through the LKB1‐AMPK‐mTOR pathway by sustaining the levels of Bcl‐2/XL and P27 (Xie et al ., 2011a; Liu et al ., 2012).…”

Section: Resultsmentioning

confidence: 99%

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Zou

Fei

et al. 2016

Aging Cell

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SummaryAutophagy is a cellular process that executes the turnover of dysfunctional organelles and misfolded or abnormally aggregated proteins. Microtubule‐associated protein MAP1S interacts with autophagy marker LC3 and positively regulates autophagy flux. LC3 binds with fibronectin mRNA and facilitates its translation. The synthesized fibronectin protein is exported to cell surface to initiate the assembly of fibronectin extracellular matrix. Fibronectin is degraded in lysosomes after it is engulfed into cytosol via endocytosis. Here, we show that defects in MAP1S‐mediated autophagy trigger oxidative stress, sinusoidal dilation, and lifespan reduction. Overexpression of LC3 in wild‐type mice increases the levels of fibronectin and γ‐H2 AX, a marker of DNA double‐strand breakage. LC3‐induced fibronectin is efficiently degraded in lysosomes to maintain a balance of fibronectin levels in wild‐type mice so that the mice live a normal term of lifespan. In the LC3 transgenic mice with MAP1S deleted, LC3 enhances the synthesis of fibronectin but the MAP1S depletion causes an impairment of the lysosomal degradation of fibronectin. The accumulation of fibronectin protein promotes liver fibrosis, induces an accumulation of cell population at the G0/G1 stage, and further intensifies oxidative stress and sinusoidal dilatation. The LC3‐induced overexpression of fibronectin imposes stresses on MAP1S‐deficient mice and dramatically reduces their lifespans. Therefore, MAP1S‐mediated autophagy plays an important role in maintaining mouse lifespan especially in the presence of extra amount of fibronectin.

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Section: Resultsmentioning

confidence: 99%

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Zou

Fei

et al. 2016

Aging Cell

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“…Beclin1 also interacts with the other major anti-apoptotic Bcl family protein (Bcl-xL) and this interaction has been shown to regulate autophagy so that not only does Bcl-2/ Bcl-xL inhibit apoptosis by binding to and interfering with the action of the pro-apoptotic proteins Bax and Bak, it also inhibits autophagy by binding with Beclin 1 and this interaction is important in the regulation of starvation-induced autophagy (69). There may however be differences in the regulation of these pathways depending on subcellular localization -Bcl-2 is found at the mitochondria and the ER however the autophagy inhibition function of Bcl-2 occurs only at the ER and mitochondrial targeted Bcl-2, which is a potent inhibitor of many apoptotic stimuli (70), cannot inhibit autophagy (69). Recent work from several groups has focused on further analysis of the Beclin 1-Bcl-2/Bcl-xL interaction.…”

Section: Molecular Connections Between Autophagy and Apoptosismentioning

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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“…Interestingly, Beclin-1 is required for ATG7-dependent and ATG7-independent autophagy [72]. Beclin-1 also regulates apoptosis by interacting with both BCL2 and BCL2L1/BCL-XL [73]. Additionally, apoptosis may inhibit autophagy as CAPN/calpain cleaves ATG5, which triggers CASP-dependent cell death [71,74].…”

Section: Discussionmentioning

confidence: 99%

Autophagy enhances the replication of Peste des petits ruminants virus and inhibits caspase-dependent apoptosis in vitro

Yang

Xue

et al. 2018

Virulence

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Peste des petits ruminants (PPR) is an acute and highly contagious disease in small ruminants that causes significant economic losses in developing countries. An increasing number of studies have demonstrated that both autophagy and apoptosis are important cellular mechanisms for maintaining homeostasis, and they participate in the host response to pathogens. However, the crosstalk between apoptosis and autophagy in host cells during PPRV infection has not been clarified. In this study, autophagy was induced upon virus infection in caprine endometrial epithelial cells (EECs), as determined by the appearance of double- and single-membrane autophagy-like vesicles, LC3-I/LC3-II conversion, and p62 degradation. We also found that PPRV infection triggered a complete autophagic response, most likely mediated by the non-structural protein C and nucleoprotein N. Moreover, our results suggest that autophagy not only promotes the replication of PPRV in EECs but also provides a potential mechanism for inhibiting PPRV-induced apoptosis. Inhibiting autophagosome formation by wortmannin and knocking down the essential autophagic proteins Beclin-1 and ATG7 induces caspase-dependent apoptosis in EECs in PPRV infection. However, inhibiting autophagosome and lysosome fusion by NH4Cl and chloroquine did not increase the number of apoptotic cells. Collectively, these data are the first to indicate that PPRV-induced autophagy inhibits caspase-dependent apoptosis and thus contributes to the enhancement of viral replication and maturity in host cells.

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Bcl-2 Antiapoptotic Proteins Inhibit Beclin 1-Dependent Autophagy

Cited by 3,227 publications

References 39 publications

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Defects in MAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Apoptosis and autophagy: regulatory connections between two supposedly different processes

Autophagy enhances the replication of Peste des petits ruminants virus and inhibits caspase-dependent apoptosis in vitro

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