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Zhenyu Yue - One of the best experts on this subject based on the ideXlab platform.
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targeting the potent Beclin 1 uvrag coiled coil interaction with designed peptides enhances autophagy and endolysosomal trafficking
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Xianxiu Qiu, Zhenyu Yue, Wenchao Yang, Wenchao Liu, Hanming Shen, Renxiao Wang, Yanxiang ZhaoAbstract:The Beclin 1–Vps34 complex, known as “mammalian class III PI3K,” plays essential roles in membrane-mediated transport processes including autophagy and endosomal trafficking. Beclin 1 acts as a scaffolding molecule for the complex and readily transits from its metastable homodimeric state to interact with key modulators such as Atg14L or UVRAG and form functionally distinct Atg14L/UVRAG-containing Beclin 1–Vps34 subcomplexes. The Beclin 1–Atg14L/UVRAG interaction relies critically on their coiled-coil domains, but the molecular mechanism remains poorly understood. We determined the crystal structure of Beclin 1–UVRAG coiled-coil complex and identified a strengthened interface with both hydrophobic pairings and electrostatically complementary interactions. This structure explains why the Beclin 1–UVRAG interaction is more potent than the metastable Beclin 1 homodimer. Potent Beclin 1–UVRAG interaction is functionally significant because it renders UVRAG more competitive than Atg14L in Beclin 1 binding and is critical for promoting endolysosomal trafficking. UVRAG coiled-coil mutants with weakened Beclin 1 binding do not outcompete Atg14L and fail to promote endolysosomal degradation of the EGF receptor (EGFR). We designed all-hydrocarbon stapled peptides that specifically targeted the C-terminal part of the Beclin 1 coiled-coil domain to interfere with its homodimerization. One such peptide reduced Beclin 1 self-association, promoted Beclin 1–Atg14L/UVRAG interaction, increased autophagic flux, and enhanced EGFR degradation. Our results demonstrate that the targeting Beclin 1 coiled-coil domain with designed peptides to induce the redistribution of Beclin 1 among its self-associated form or Atg14L/UVRAG-containing complexes enhances both autophagy and endolysosomal trafficking.
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Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex
PLoS genetics, 2014Co-Authors: Nicole C. Mcknight, Nathaniel Heintz, Yun Zhong, Mitchell S. Wold, Shiaoching Gong, Greg R. Phillips, Zhixun Dou, Yanxiang Zhao, Wei-xing Zong, Zhenyu YueAbstract:Deficiency of autophagy protein Beclin 1 is implicated in tumorigenesis and neurodegenerative diseases, but the molecular mechanism remains elusive. Previous studies showed that Beclin 1 coordinates the assembly of multiple VPS34 complexes whose distinct phosphatidylinositol 3-kinase III (PI3K-III) lipid kinase activities regulate autophagy at different steps. Recent evidence suggests a function of Beclin 1 in regulating multiple VPS34-mediated trafficking pathways beyond autophagy; however, the precise role of Beclin 1 in autophagy-independent cellular functions remains poorly understood. Herein we report that Beclin 1 regulates endocytosis, in addition to autophagy, and is required for neuron viability in vivo. We find that neuronal Beclin 1 associates with endosomes and regulates EEA1/early endosome localization and late endosome formation. Beclin 1 maintains proper cellular phosphatidylinositol 3-phosphate (PI(3)P) distribution and total levels, and loss of Beclin 1 causes a disruption of active Rab5 GTPase-associated endosome formation and impairment of endosome maturation, likely due to a failure of Rab5 to recruit VPS34. Furthermore, we find that Beclin 1 deficiency causes complete loss of the UVRAG-VPS34 complex and associated lipid kinase activity. Interestingly, Beclin 1 deficiency impairs p40phox-linked endosome formation, which is rescued by overexpressed UVRAG or Beclin 1, but not by a coiled-coil domain-truncated Beclin 1 (a UVRAG-binding mutant), Atg14L or RUBICON. Thus, our study reveals the essential role for Beclin 1 in neuron survival involving multiple membrane trafficking pathways including endocytosis and autophagy, and suggests that the UVRAG-Beclin 1 interaction underlies Beclin 1's function in endocytosis.
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Involvement of Beclin 1 in Engulfment of Apoptotic Cells
The Journal of biological chemistry, 2012Co-Authors: Akimitsu Konishi, Zhenyu Yue, Satoko Arakawa, Shigeomi ShimizuAbstract:Efficient apoptotic cell engulfment is important for both tissue homeostasis and immune response in mammals. In the present study, we report that Beclin 1 (a regulator of autophagy) is required for apoptotic cell engulfment. The engulfment process was largely abolished in Beclin 1 knock-out cells, and Beclin 1 knockdown significantly decreased apoptotic cell internalization in macrophage and fibroblast cell lines. Beclin 1 was recruited to the early phagocytic cup along with the generation of phosphatidylinositol 3-phosphate and Rac1, which regulates actin dynamics in lamellipodia. No lamellipodia were formed in Beclin 1 knock-out cells, and Beclin 1 knockdown completely inhibited the promotion of engulfment by ectopic expression of Rac1. Beclin 1 was co-immunoprecipitated with Rac1. These data indicate that Beclin 1 coordinates actin dynamics and membrane phospholipid synthesis to promote efficient apoptotic cell engulfment.
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the Beclin 1 vps34 complex at the crossroads of autophagy and beyond
Trends in Cell Biology, 2010Co-Authors: Sarah F. Funderburk, Qing Jun Wang, Zhenyu YueAbstract: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.
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The Beclin 1–VPS34 complex – at the crossroads of autophagy and beyond
Trends in cell biology, 2010Co-Authors: Sarah F. Funderburk, Qing Jun Wang, Zhenyu YueAbstract: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.
Clarisse Berlioz-torrent - One of the best experts on this subject based on the ideXlab platform.
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Beclin-1 is required for chromosome congression and proper outer kinetochore assembly.
EMBO Reports, 2013Co-Authors: Stéphane Frémont, Annabelle Gérard, Marie Galloux, Katy Janvier, Roger E Karess, Clarisse Berlioz-torrentAbstract:The functions of Beclin-1 in macroautophagy, tumorigenesis and cytokinesis are thought to be mediated by its association with the PI3K-III complex. Here, we describe a new role for Beclin-1 in mitotic chromosome congression that is independent of the PI3K-III complex and its role in autophagy. Beclin-1 depletion in HeLa cells leads to a significant reduction of the outer kinetochore proteins CENP-E, CENP-F and ZW10, and, consequently, the cells present severe problems in chromosome congression. Beclin-1 associates with kinetochore microtubules and forms discrete foci near the kinetochores of attached chromosomes. We show that Beclin-1 interacts directly with Zwint-1-a component of the KMN (KNL-1/Mis12/Ndc80) complex-which is essential for kinetochore-microtubule interactions. This suggests that Beclin-1 acts downstream of the KMN complex to influence the recruitment of outer kinetochore proteins and promotes accurate kinetochore anchoring to the spindle during mitosis.
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Beclin‐1 is required for chromosome congression and proper outer kinetochore assembly
EMBO reports, 2013Co-Authors: Stéphane Frémont, Annabelle Gérard, Marie Galloux, Katy Janvier, Roger E Karess, Clarisse Berlioz-torrentAbstract:The functions of Beclin-1 in macroautophagy, tumorigenesis and cytokinesis are thought to be mediated by its association with the PI3K-III complex. Here, we describe a new role for Beclin-1 in mitotic chromosome congression that is independent of the PI3K-III complex and its role in autophagy. Beclin-1 depletion in HeLa cells leads to a significant reduction of the outer kinetochore proteins CENP-E, CENP-F and ZW10, and, consequently, the cells present severe problems in chromosome congression. Beclin-1 associates with kinetochore microtubules and forms discrete foci near the kinetochores of attached chromosomes. We show that Beclin-1 interacts directly with Zwint-1—a component of the KMN (KNL-1/Mis12/Ndc80) complex—which is essential for kinetochore–microtubule interactions. This suggests that Beclin-1 acts downstream of the KMN complex to influence the recruitment of outer kinetochore proteins and promotes accurate kinetochore anchoring to the spindle during mitosis.
David C. Rubinsztein - One of the best experts on this subject based on the ideXlab platform.
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VCP/p97 regulates Beclin-1-dependent autophagy initiation
Nature Chemical Biology, 2021Co-Authors: Sandra M. Hill, Lidia Wrobel, Avraham Ashkenazi, Marian Fernandez-estevez, Keith Tan, Roland W. Bürli, David C. RubinszteinAbstract:Autophagy is an essential cellular process that removes harmful protein species, and autophagy upregulation may be able to protect against neurodegeneration and various pathogens. Here, we have identified the essential protein VCP/p97 (VCP, valosin-containing protein) as a novel regulator of autophagosome biogenesis, where VCP regulates autophagy induction in two ways, both dependent on Beclin-1. Utilizing small-molecule inhibitors of VCP ATPase activity, we show that VCP stabilizes Beclin-1 levels by promoting the deubiquitinase activity of ataxin-3 towards Beclin-1. VCP also regulates the assembly and activity of the Beclin-1-containing phosphatidylinositol-3-kinase (PI3K) complex I, thus regulating the production of PI(3)P, a key signaling lipid responsible for the recruitment of downstream autophagy factors. A decreased level of VCP, or inhibition of its ATPase activity, impairs starvation-induced production of PI(3)P and limits downstream recruitment of WIPI2, ATG16L and LC3, thereby decreasing autophagosome formation, illustrating an important role for VCP in early autophagy initiation. The essential protein VCP/p97 regulates autophagosome formation by promoting the deubiquitinase activity of ataxin-3 toward Beclin-1 and also by regulating the assembly of the Beclin-1–PI3K complex I.
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vcp p97 regulates Beclin 1 dependent autophagy initiation
Nature Chemical Biology, 2021Co-Authors: Sandra M. Hill, Lidia Wrobel, Avraham Ashkenazi, Keith Tan, Roland W. Bürli, Marian Fernandezestevez, David C. RubinszteinAbstract:Autophagy is an essential cellular process that removes harmful protein species, and autophagy upregulation may be able to protect against neurodegeneration and various pathogens. Here, we have identified the essential protein VCP/p97 (VCP, valosin-containing protein) as a novel regulator of autophagosome biogenesis, where VCP regulates autophagy induction in two ways, both dependent on Beclin-1. Utilizing small-molecule inhibitors of VCP ATPase activity, we show that VCP stabilizes Beclin-1 levels by promoting the deubiquitinase activity of ataxin-3 towards Beclin-1. VCP also regulates the assembly and activity of the Beclin-1-containing phosphatidylinositol-3-kinase (PI3K) complex I, thus regulating the production of PI(3)P, a key signaling lipid responsible for the recruitment of downstream autophagy factors. A decreased level of VCP, or inhibition of its ATPase activity, impairs starvation-induced production of PI(3)P and limits downstream recruitment of WIPI2, ATG16L and LC3, thereby decreasing autophagosome formation, illustrating an important role for VCP in early autophagy initiation.
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bim inhibits autophagy by recruiting Beclin 1 to microtubules
Molecular Cell, 2012Co-Authors: Shouqing Luo, Moises Garciaarencibia, Rui Zhao, Claudia Puri, Pearl P C Toh, Oana Sadiq, David C. RubinszteinAbstract:Bim is a proapoptotic BH3-only Bcl-2 family member. In response to death stimuli, Bim dissociates from the dynein light chain 1 (DYNLL1/LC8), where it is inactive, and can then initiate Bax/Bak-mediated mitochondria-dependent apoptosis. We found that Bim depletion increases autophagosome synthesis in cells and in vivo, and this effect is inhibited by overexpression of cell death-deficient Bim. Bim inhibits autophagy by interacting with Beclin 1, an autophagy regulator, and this interaction is facilitated by LC8. Bim bridges the Beclin 1-LC8 interaction and thereby inhibits autophagy by mislocalizing Beclin 1 to the dynein motor complex. Starvation, an autophagic stimulus, induces Bim phosphorylation, which abrogates LC8 binding to Bim, leading to dissociation of Bim and Beclin 1. Our data suggest that Bim switches locations between apoptosis-inactive/autophagy-inhibitory and apoptosis-active/autophagy-permissive sites.
Beth Levine - One of the best experts on this subject based on the ideXlab platform.
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akt mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation
Science, 2012Co-Authors: Richard C Wang, Yongjie Wei, Zhongju Zou, Guanghua Xiao, Govind Bhagat, Michael A White, Julia Reichelt, Beth LevineAbstract:Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)-Akt axis is frequent in human cancer. Here, we show that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt. Expression of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation. Thus, Akt-mediated phosphorylation of Beclin 1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory Beclin 1/14-3-3/vimentin intermediate filament complex. These findings have broad implications for understanding the role of Akt signaling and intermediate filament proteins in autophagy and cancer.
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The Beclin 1 interactome.
Current opinion in cell biology, 2010Co-Authors: Beth LevineAbstract: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-XL, 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.
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Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.
Cell, 2005Co-Authors: Sophie Pattingre, Noboru Mizushima, Amina T. Tassa, Rita Garuti, Xiao Huan Liang, Milton Packer, Michael D. Schneider, Beth LevineAbstract:Apoptosis and autophagy are both tightly regulated biological processes that play a central role in tissue homeostasis, development, and disease. The anti-apoptotic protein, Bcl-2, interacts with the evolutionarily conserved autophagy protein, Beclin 1. However, little is known about the functional significance of this interaction. Here, we show that wild-type Bcl-2 antiapoptotic proteins, but not Beclin 1 binding defective mutants of Bcl-2, inhibit Beclin 1-dependent autophagy in yeast and mammalian cells and that cardiac Bcl-2 transgenic expression inhibits autophagy in mouse heart muscle. Furthermore, Beclin 1 mutants that cannot bind to Bcl-2 induce more autophagy than wild-type Beclin 1 and, unlike wild-type Beclin 1, promote cell death. Thus, Bcl-2 not only functions as an antiapoptotic protein, but also as an antiautophagy protein via its inhibitory interaction with Beclin 1. This antiautophagy function of Bcl-2 may help maintain autophagy at levels that are compatible with cell survival, rather than cell death.
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Induction of autophagy and inhibition of tumorigenesis by Beclin 1
Nature, 1999Co-Authors: Xiao Huan Liang, Hanina Hibshoosh, Saadiya Jackson, Matthew Seaman, Kristy Brown, Bettina Kempkes, Beth LevineAbstract:The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway^ 1 , is important in normal growth control and may be defective in tumour cells^ 2 . However, little is known about the genetic mediators of autophagy in mammalian cells or their role in tumour development. The mammalian gene encoding Beclin 1 (ref. 3 ), a novel Bcl-2-interacting, coiled-coil protein, has structural similarity to the yeast autophagy gene, apg6/vps30 (refs 4 , 5 ), and is mono-allelically deleted in 40–75% of sporadic human breast cancers and ovarian cancers^ 6 . Here we show, using gene-transfer techniques, that Beclin 1 promotes autophagy in autophagy-defective yeast with a targeted disruption of agp6/vps30 , and in human MCF7 breast carcinoma cells. The autophagy-promoting activity of Beclin 1 in MCF7 cells is associated with inhibition of MCF7 cellular proliferation, in vitro clonigenicity and tumorigenesis in nude mice. Furthermore, endogenous Beclin 1 protein expression is frequently low in human breast epithelial carcinoma cell lines and tissue, but is expressed ubiquitously at high levels in normal breast epithelia. Thus, Beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma. These findings suggest that decreased expression of autophagy proteins may contribute to the development or progression of breast and other human malignancies.
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Induction of autophagy and inhibition of tumorigenesis by Beclin 1.
Nature, 1999Co-Authors: Xiao Huan Liang, Hanina Hibshoosh, Saadiya Jackson, Kristy Brown, Bettina Kempkes, Matthew N.j. Seaman, Beth LevineAbstract:The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway, is important in normal growth control and may be defective in tumour cells. However, little is known about the genetic mediators of autophagy in mammalian cells or their role in tumour development. The mammalian gene encoding Beclin 1, a novel Bcl-2-interacting, coiled-coil protein, has structural similarity to the yeast autophagy gene, apg6/vps30, and is mono-allelically deleted in 40-75% of sporadic human breast cancers and ovarian cancers. Here we show, using gene-transfer techniques, that Beclin 1 promotes autophagy in autophagy-defective yeast with a targeted disruption of agp6/vps30, and in human MCF7 breast carcinoma cells. The autophagy-promoting activity of Beclin 1 in MCF7 cells is associated with inhibition of MCF7 cellular proliferation, in vitro clonigenicity and tumorigenesis in nude mice. Furthermore, endogenous Beclin 1 protein expression is frequently low in human breast epithelial carcinoma cell lines and tissue, but is expressed ubiquitously at high levels in normal breast epithelia. Thus, Beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma. These findings suggest that decreased expression of autophagy proteins may contribute to the development or progression of breast and other human malignancies.
Stéphane Frémont - One of the best experts on this subject based on the ideXlab platform.
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Beclin-1 is required for chromosome congression and proper outer kinetochore assembly.
EMBO Reports, 2013Co-Authors: Stéphane Frémont, Annabelle Gérard, Marie Galloux, Katy Janvier, Roger E Karess, Clarisse Berlioz-torrentAbstract:The functions of Beclin-1 in macroautophagy, tumorigenesis and cytokinesis are thought to be mediated by its association with the PI3K-III complex. Here, we describe a new role for Beclin-1 in mitotic chromosome congression that is independent of the PI3K-III complex and its role in autophagy. Beclin-1 depletion in HeLa cells leads to a significant reduction of the outer kinetochore proteins CENP-E, CENP-F and ZW10, and, consequently, the cells present severe problems in chromosome congression. Beclin-1 associates with kinetochore microtubules and forms discrete foci near the kinetochores of attached chromosomes. We show that Beclin-1 interacts directly with Zwint-1-a component of the KMN (KNL-1/Mis12/Ndc80) complex-which is essential for kinetochore-microtubule interactions. This suggests that Beclin-1 acts downstream of the KMN complex to influence the recruitment of outer kinetochore proteins and promotes accurate kinetochore anchoring to the spindle during mitosis.
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Beclin‐1 is required for chromosome congression and proper outer kinetochore assembly
EMBO reports, 2013Co-Authors: Stéphane Frémont, Annabelle Gérard, Marie Galloux, Katy Janvier, Roger E Karess, Clarisse Berlioz-torrentAbstract:The functions of Beclin-1 in macroautophagy, tumorigenesis and cytokinesis are thought to be mediated by its association with the PI3K-III complex. Here, we describe a new role for Beclin-1 in mitotic chromosome congression that is independent of the PI3K-III complex and its role in autophagy. Beclin-1 depletion in HeLa cells leads to a significant reduction of the outer kinetochore proteins CENP-E, CENP-F and ZW10, and, consequently, the cells present severe problems in chromosome congression. Beclin-1 associates with kinetochore microtubules and forms discrete foci near the kinetochores of attached chromosomes. We show that Beclin-1 interacts directly with Zwint-1—a component of the KMN (KNL-1/Mis12/Ndc80) complex—which is essential for kinetochore–microtubule interactions. This suggests that Beclin-1 acts downstream of the KMN complex to influence the recruitment of outer kinetochore proteins and promotes accurate kinetochore anchoring to the spindle during mitosis.