Journal
JOURNAL OF CELL SCIENCE
Volume 128, Issue 15, Pages 2938-2950Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.173807
Keywords
MITF; TFEB; TORC1; Gut; Melanocytes; v-ATPase
Categories
Funding
- National Institutes of Health, National Eye Institute [R01EY017097]
- RPB Unrestricted Grant and Lions District [20-Y1]
- Icelandic Research Fund [130230-053, 152715-051]
- PHC Jules Verne grant [31891VM]
- Ligue Nationale Contre le Cancer (Equipe labellisee)
- INCa
- Canceropole
- Ile de France
- Labex CelTisPhyBio [ANR-11-LBX-0038]
- Ludwig Institute for Cancer Research
- Harry J Lloyd Trust
- NATIONAL EYE INSTITUTE [R01EY017097] Funding Source: NIH RePORTER
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The v-ATPase is a fundamental eukaryotic enzyme that is central to cellular homeostasis. Although its impact on key metabolic regulators such as TORC1 is well documented, our knowledge of mechanisms that regulate v-ATPase activity is limited. Here, we report that the Drosophila transcription factor Mitf is a master regulator of this holoenzyme. Mitf directly controls transcription of all 15 v-ATPase components through M-box cis-sites and this coordinated regulation affects holoenzyme activity in vivo. In addition, through the v-ATPase, Mitf promotes the activity of TORC1, which in turn negatively regulates Mitf. We provide evidence that Mitf, v-ATPase and TORC1 form a negative regulatory loop that maintains each of these important metabolic regulators in relative balance. Interestingly, direct regulation of v-ATPase genes by human MITF also occurs in cells of the melanocytic lineage, showing mechanistic conservation in the regulation of the v-ATPase by MITF family proteins in fly and mammals. Collectively, this evidence points to an ancient module comprising Mitf, v-ATPase and TORC1 that serves as a dynamic modulator of metabolism for cellular homeostasis.
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