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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Autophagy is typically dependent on vacuolar acidity maintained by the vacuolar-type H+-translocating ATPase (V-ATPase).
  • The V-ATPase is primarily viewed as a proton pump essential for lysosomal degradation.
  • Existing research assumes V-ATPase inhibitors are neutral markers of autophagy flux.

Purpose of the Study:

  • To investigate the role of V-ATPase activity in regulating autophagy.
  • To challenge the established paradigm of V-ATPase function in cellular degradation.
  • To explore the signaling pathways involved in V-ATPase-regulated autophagy.

Main Methods:

  • Utilized *Saccharomyces cerevisiae* (yeast) as a model organism.
  • Investigated autophagy induction under conditions of V-ATPase inhibition or dysfunction.
  • Analyzed signaling cascades involving the Gcn2-Gcn4/ATF4 integrated stress response.
  • Examined the role of Atg11 in V-ATPase-dependent autophagy and ribophagy.
  • Assessed the impact of tryptophan and NAD+ metabolism on autophagy induction.

Main Results:

  • Loss of V-ATPase activity paradoxically induces selective autophagy, specifically ribophagy, in nutrient-replete yeast.
  • Vacuolar deacidification triggers a Gcn2-Gcn4/ATF4 integrated stress response, driving autophagy even when TORC1 is active.
  • This V-ATPase-dependent autophagy functions as a feedback mechanism to signal vacuolar dysfunction and restore homeostasis.
  • Tryptophan and NAD+ metabolism were found to modulate this autophagy response.
  • V-ATPase inhibition can stimulate autophagy induction, challenging its use as a neutral flux marker.

Conclusions:

  • The V-ATPase is not merely a proton pump but an active sensor of cellular integrity and a regulator of autophagy.
  • V-ATPase-dependent autophagy represents a novel self-corrective feedback loop for maintaining cellular homeostasis.
  • The findings necessitate a re-evaluation of V-ATPase inhibitors in autophagy research.
  • This study reframes the vacuole/lysosome's role from a passive degradation site to an active cellular signaling hub.