Autophagy is an evolutionary conserved catabolic process involved in several physiological and pathological processes such as cancer and neurodegeneration. 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.

The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy / Di Bartolomeo, Sabrina; Corazzari, Marco; Nazio, Francesca; Oliverio, Serafina; Lisi, Gaia; Antonioli, Manuela; Pagliarini, Vittoria; Matteoni, Silvia; Fuoco, Claudia; Giunta, Luigi; D'Amelio, Marcello; Nardacci, Roberta; Romagnoli, Alessandra; Piacentini, Mauro; Cecconi, Francesco; Fimia, Gian Maria. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 191:1(2010), pp. 155-168. [10.1083/jcb.201002100]

The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy

FIMIA, Gian Maria
2010

Abstract

Autophagy is an evolutionary conserved catabolic process involved in several physiological and pathological processes such as cancer and neurodegeneration. 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.
2010
Adaptor Proteins; Signal Transducing; Apoptosis Regulatory Proteins; Autophagy; Carrier Proteins; Cells; Cultured; Down-Regulation; Dyneins; Endoplasmic Reticulum; GTPase-Activating Proteins; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Phosphorylation; Protein-Serine-Threonine Kinases; RNA Interference; Signal Transduction; Tumor Suppressor Proteins
01 Pubblicazione su rivista::01a Articolo in rivista
The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy / Di Bartolomeo, Sabrina; Corazzari, Marco; Nazio, Francesca; Oliverio, Serafina; Lisi, Gaia; Antonioli, Manuela; Pagliarini, Vittoria; Matteoni, Silvia; Fuoco, Claudia; Giunta, Luigi; D'Amelio, Marcello; Nardacci, Roberta; Romagnoli, Alessandra; Piacentini, Mauro; Cecconi, Francesco; Fimia, Gian Maria. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 191:1(2010), pp. 155-168. [10.1083/jcb.201002100]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1319393
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