V-ATPase: a master effector of E2F1-mediated lysosomal trafficking, mTORC1 activation and autophagy
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Nathalie Meo-Evoli1,2, Eugènia Almacellas1,2, Francesco Alessandro Massucci3, Antonio Gentilella2, Santiago Ambrosio4, Sara C. Kozma2,5,6, George Thomas2,4,5,6, Albert Tauler1,2
1Departament de Bioquímica i Biologia Molecular, Facultat de Farmàcia, Universitat de Barcelona, 08028 Barcelona, Catalunya, Spain
2Laboratory of Cancer Metabolism, IDIBELL, Hospital Duran i Reynals, 08908 L’Hospitalet de Llobregat, Barcelona, Catalunya, Spain
3Departament d’Enginyeria Química, Universitat Rovira i Virgili, 43007 Tarragona, Catalunya, Spain
4Unitat de Bioquímica, Dep. Ciències Fisiològiques II, Facultat de Medicina, Campus Universitari de Bellvitge - IDIBELL, Universitat de Barcelona, 08908 L’Hospitalet de Llobregat, Barcelona, Catalunya, Spain
5Laboratory of Cancer Metabolism, Institut Català d’Oncologia, Hospital Duran i Reynals, 08908 L’Hospitalet de Llobregat, Barcelona, Catalunya, Spain
6Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA
Albert Tauler, e-mail: firstname.lastname@example.org
Keywords: E2F1, v-ATPase, mTORC1, autophagy, lysosomes
Received: March 17, 2015 Accepted: July 30, 2015 Published: August 11, 2015
In addition to being a master regulator of cell cycle progression, E2F1 regulates other associated biological processes, including growth and malignancy. Here, we uncover a regulatory network linking E2F1 to lysosomal trafficking and mTORC1 signaling that involves v-ATPase regulation. By immunofluorescence and time-lapse microscopy we found that E2F1 induces the movement of lysosomes to the cell periphery, and that this process is essential for E2F1-induced mTORC1 activation and repression of autophagy. Gain- and loss-of-function experiments reveal that E2F1 regulates v-ATPase activity and inhibition of v-ATPase activity repressed E2F1-induced lysosomal trafficking and mTORC1 activation. Immunoprecipitation experiments demonstrate that E2F1 induces the recruitment of v-ATPase to lysosomal RagB GTPase, suggesting that E2F1 regulates v-ATPase activity by enhancing the association of V0 and V1 v-ATPase complex. Analysis of v-ATPase subunit expression identified B subunit of V0 complex, ATP6V0B, as a transcriptional target of E2F1. Importantly, ATP6V0B ectopic-expression increased v-ATPase and mTORC1 activity, consistent with ATP6V0B being responsible for mediating the effects of E2F1 on both responses. Our findings on lysosomal trafficking, mTORC1 activation and autophagy suppression suggest that pharmacological intervention at the level of v-ATPase may be an efficacious avenue for the treatment of metastatic processes in tumors overexpressing E2F1.
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