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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.

Original publication

DOI

10.1242/jcs.173807

Type

Journal article

Journal

J Cell Sci

Publication Date

01/08/2015

Volume

128

Pages

2938 - 2950

Keywords

Gut, MITF, Melanocytes, TFEB, TORC1, v-ATPase, Animals, Cell Line, Tumor, Cell Membrane, Drosophila, Drosophila Proteins, Enzyme Activation, Homeostasis, Humans, Melanocytes, Melanoma, Microphthalmia-Associated Transcription Factor, Mitochondrial Proton-Translocating ATPases, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering, Transcription Factors, Transcription, Genetic, Vacuolar Proton-Translocating ATPases