Journal
JOURNAL OF CELL BIOLOGY
Volume 191, Issue 1, Pages 155-168Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201002100
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Funding
- Telethon Foundation
- Advanced Imaging Research Center
- Italian Ministry of University and Research
- Italian Ministry of Health
- European Union
- Compagnia di San Paolo
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Autophagy is an evolutionary conserved catabolic process involved in several physiological and pathological processes such as cancer and neuro-degeneration. Autophagy initiation signaling requires both the ULK1 kinase and the BECLIN 1-VPS34 core complex to generate autophagosomes, double-membraned vesicles that transfer cellular contents to lysosomes. In this study, we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2. When autophagy is induced, ULK1 phosphorylates AMBRA1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Therefore, AMBRA1 constitutes a direct regulatory link between ULK1 and BECLIN 1-VPS34, which is required for core complex positioning and activity within the cell. Moreover, our results demonstrate that in addition to a function for microtubules in mediating autophagosome transport, there is a strict and regulatory relationship between cytoskeleton dynamics and autophagosome formation.
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