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To reconcile the opposite effects of V-ATPase dysfunction on autophagy flux in nutrient-rich versus starvation medium, we reasoned that dysfunction of the V-ATPase may have dual roles in autophagy regulation: On the one hand, it hampers vacuolar hydrolytic activities (but vacuolar proteases such as Pep4 are still partially active)

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Nonetheless, the underlying mechanisms of this unexpected mutational activation of autophagic flux by recurrent hotspot mutations in genes associated with V-ATPase activity remain unclear