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Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex

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)...

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Autores principales: McKnight, Nicole C., Zhong, Yun, Wold, Mitchell S., Gong, Shiaoching, Phillips, Greg R., Dou, Zhixun, Zhao, Yanxiang, Heintz, Nathaniel, Zong, Wei-Xing, Yue, Zhenyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183436/
https://www.ncbi.nlm.nih.gov/pubmed/25275521
http://dx.doi.org/10.1371/journal.pgen.1004626
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author McKnight, Nicole C.
Zhong, Yun
Wold, Mitchell S.
Gong, Shiaoching
Phillips, Greg R.
Dou, Zhixun
Zhao, Yanxiang
Heintz, Nathaniel
Zong, Wei-Xing
Yue, Zhenyu
author_facet McKnight, Nicole C.
Zhong, Yun
Wold, Mitchell S.
Gong, Shiaoching
Phillips, Greg R.
Dou, Zhixun
Zhao, Yanxiang
Heintz, Nathaniel
Zong, Wei-Xing
Yue, Zhenyu
author_sort McKnight, Nicole C.
collection PubMed
description 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 p40(phox)-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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spelling pubmed-41834362014-10-07 Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex McKnight, Nicole C. Zhong, Yun Wold, Mitchell S. Gong, Shiaoching Phillips, Greg R. Dou, Zhixun Zhao, Yanxiang Heintz, Nathaniel Zong, Wei-Xing Yue, Zhenyu PLoS Genet Research Article 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 p40(phox)-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. Public Library of Science 2014-10-02 /pmc/articles/PMC4183436/ /pubmed/25275521 http://dx.doi.org/10.1371/journal.pgen.1004626 Text en © 2014 McKnight et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
McKnight, Nicole C.
Zhong, Yun
Wold, Mitchell S.
Gong, Shiaoching
Phillips, Greg R.
Dou, Zhixun
Zhao, Yanxiang
Heintz, Nathaniel
Zong, Wei-Xing
Yue, Zhenyu
Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex
title Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex
title_full Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex
title_fullStr Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex
title_full_unstemmed Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex
title_short Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex
title_sort beclin 1 is required for neuron viability and regulates endosome pathways via the uvrag-vps34 complex
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183436/
https://www.ncbi.nlm.nih.gov/pubmed/25275521
http://dx.doi.org/10.1371/journal.pgen.1004626
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