V-ATPase-dependent induction of selective autophagy

Yuxiang Huang, Dimitra Dialynaki, Yuchen Lei, Zhihai Zhang, Charles R. Evans and Daniel J. Klionsky ()
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Yuxiang Huang: University of Michigan
Dimitra Dialynaki: University of Michigan
Yuchen Lei: University of Michigan
Zhihai Zhang: University of Michigan
Charles R. Evans: University of Michigan
Daniel J. Klionsky: University of Michigan

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The general consensus is that the vacuolar-type H+-translocating ATPase (V-ATPase) is critical for macroautophagy/autophagy. However, there is a fundamental conundrum because follicular lymphoma-associated mutations in the V-ATPase result in lysosomal/vacuolar deacidification but elevated autophagy activity under nutrient-replete conditions and the underlying mechanisms remain unclear. Here, working in yeast, we show that V-ATPase dysfunction activates a selective autophagy flux termed “V-ATPase-dependent autophagy “. By combining transcriptomic and proteomic profiling, along with genome-wide suppressor screening approaches, we found that V-ATPase-dependent autophagy is regulated through a unique mechanism distinct from classical nitrogen starvation-induced autophagy. Tryptophan metabolism negatively regulates V-ATPase-dependent autophagy via two parallel effectors. On the one hand, it activates ribosome biogenesis, thus repressing the translation of the transcription factor Gcn4/ATF4. On the other hand, tryptophan fuels NAD+ de novo biosynthesis to inhibit autophagy. These results provide an explanation for the mutational activation of autophagy seen in follicular lymphoma patients.

Date: 2025
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DOI: 10.1038/s41467-025-63472-5

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