Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/36226
Title: Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex
Authors: McKnight, NC
Zhong, Y
Wold, MS
Gong, SC
Phillips, GR
Dou, ZX
Zhao, YX 
Heintz, N
Zong, WX
Yue, ZY
Issue Date: 2014
Publisher: Public Library of Science
Source: Plos genetics, 2014, v. 10, no. 10, e1004626 How to cite?
Journal: Plos genetics 
Abstract: 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.
URI: http://hdl.handle.net/10397/36226
ISSN: 1553-7390 (print)
1553-7404 (online)
DOI: 10.1371/journal.pgen.1004626
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