TY - JOUR
T1 - The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy
AU - Di Bartolomeo, Sabrina
AU - Corazzari, Marco
AU - Nazio, Francesca
AU - Oliverio, Serafina
AU - Lisi, Gaia
AU - Antonioli, Manuela
AU - Pagliarini, Vittoria
AU - Matteoni, Silvia
AU - Fuoco, Claudia
AU - Giunta, Luigi
AU - D'Amelio, Marcello
AU - Nardacci, Roberta
AU - Romagnoli, Alessandra
AU - Piacentini, Mauro
AU - Cecconi, Francesco
AU - Fimia, Gian Maria
PY - 2010/10/4
Y1 - 2010/10/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77957728513&partnerID=8YFLogxK
U2 - 10.1083/jcb.201002100
DO - 10.1083/jcb.201002100
M3 - Article
SN - 0021-9525
VL - 191
SP - 155
EP - 168
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 1
ER -