Abstract
Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP3R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy.
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Abbreviations
- Ambra1:
-
activating molecule in Beclin 1-regulated autophagy
- BH:
-
Bcl-2-homology
- Bif-1:
-
endophilin B1/Bax-interacting factor 1
- CCD:
-
coiled-coil domain
- Cdk1:
-
cyclin-dependent kinase 1
- DAPK:
-
death-associated protein kinase
- ER:
-
endoplasmic reticulum
- ECD:
-
evolutionarily conserved domain
- ERK:
-
extracellular signal-regulated kinase
- GluRδ2:
-
glutamate receptor δ2
- HMGB1:
-
high mobility group box 1
- IP3:
-
inositol-1,4,5 trisphosphate
- JNK:
-
c-Jun N-terminal kinase
- LC3:
-
microtubule-associated protein light chain 3
- mTOR:
-
mammalian target of rapamycin
- NES:
-
nuclear export signal
- NAF-1:
-
nutrient-deprivation autophagy factor-1
- nPIST:
-
neuronal isoform of protein-interaction, specifically with TC10
- NF-κB:
-
nuclear factor-κB
- PI3KC3:
-
class III type phosphoinositide 3-kinase
- PAS:
-
pre-autophagosomal structure
- PINK1:
-
PTEN-induced putative kinase 1
- ROS:
-
reactive oxygen species
- RAGE:
-
receptor for advanced glycation end products
- Rubicon:
-
RUN domain protein as Beclin 1 interacting and cysteine-rich containing
- TRAF6:
-
tumor necrosis factor receptor-associated factor 6
- TP53INP2:
-
tumor protein 53-induced nuclear protein 2
- TLR:
-
Toll-like receptor
- UVRAG:
-
UV radiation resistance-associated gene
- Vps:
-
vacuolar protein sorting
- VMP1:
-
vacuole membrane protein 1
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Acknowledgements
We thank the numerous colleagues in the field of autophagy, who through their animated discussions have helped shape this review. We would particularly like to thank Dr. Beth Levine who generously critiqued the article and improved it based on her insights and pioneering work in the area of Beclin 1 biology. We also thank Christine Heiner for careful editing of the paper. The development of a metabolism and mitochondria in disease working group with Dr. Bennett Van Houten, who has provided reflection and encouragement for our studies is appreciated. Work in our laboratory is generously supported by the University of Pittsburgh Department of Surgery (Dr. Timothy Billiar), the University of Pittsburgh Cancer Institute (Dr. Nancy Davidson) and the National Institutes of Health via a grant from the National Cancer Institute (P01 CA 101944-04 to Michael T Lotze, MD).
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Kang, R., Zeh, H., Lotze, M. et al. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 18, 571–580 (2011). https://doi.org/10.1038/cdd.2010.191
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DOI: https://doi.org/10.1038/cdd.2010.191
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