Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex.

TitleBeclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex.
Publication TypeJournal Article
Year of Publication2014
AuthorsMcKnight NC, Zhong Y, Wold MS, Gong S, Phillips GR, Dou Z, Zhao Y, Heintz N, Zong W-X, Yue Z
JournalPLoS Genet
Date Published2014 Oct
KeywordsAnimals, Apoptosis Regulatory Proteins, Autophagy, Beclin-1, Class III Phosphatidylinositol 3-Kinases, Endocytosis, Endosomes, HeLa Cells, Humans, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Multiprotein Complexes, Neurodegenerative Diseases, Neurons, Phosphatidylinositol Phosphates, rab5 GTP-Binding Proteins, Receptor, Epidermal Growth Factor, Tumor Suppressor Proteins

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.

Alternate JournalPLoS Genet.
PubMed ID25275521
PubMed Central IDPMC4183436
Grant ListR01GM97355 / GM / NIGMS NIH HHS / United States
R01 GM097355 / GM / NIGMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
5R01NS060123-04 / NS / NINDS NIH HHS / United States
R01 NS060123 / NS / NINDS NIH HHS / United States
R01 CA129536 / CA / NCI NIH HHS / United States