Atg5 Disassociates the V1V0-ATPase to Promote Exosome Production and Tumor Metastasis Independent of Canonical Macroautophagy

Publication date: 18 December 2017
Source:Developmental Cell, Volume 43, Issue 6
Author(s): Huishan Guo, Maneka Chitiprolu, Luc Roncevic, Charlotte Javalet, Fiona J. Hemming, My Tran Trung, Lingrui Meng, Elyse Latreille, Christiano Tanese de Souza, Danielle McCulloch, R. Mitchell Baldwin, Rebecca Auer, Jocelyn Côté, Ryan Charles Russell, Rémy Sadoul, Derrick Gibbings
Autophagy and autophagy-related genes (Atg) have been attributed prominent roles in tumorigenesis, tumor growth, and metastasis. Extracellular vesicles called exosomes are also implicated in cancer metastasis. Here, we demonstrate that exosome production is strongly reduced in cells lacking Atg5 and Atg16L1, but this is independent of Atg7 and canonical autophagy. Atg5 specifically decreases acidification of late endosomes where exosomes are produced, disrupting the acidifying V1V0-ATPase by removing a regulatory component, ATP6V1E1, into exosomes. The effect of Atg5 on exosome production promotes the migration and in vivo metastasis of orthotopic breast cancer cells. These findings uncover mechanisms controlling exosome release and identify means by which autophagy-related genes can contribute to metastasis in autophagy-independent pathways.

Graphical abstract

Teaser

Guo et al. demonstrate that, independent of canonical autophagy, Atg5 and Atg16L1 de-acidify multivesicular bodies via V1V0-ATPase control to induce exosome release and promote cancer cell metastasis. This reveals mechanisms governing exosome release and suggests that some effects of Atg5 and Atg16L1 in disease are mediated by exosomes rather than autophagy.


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