Mitf Is a Master Regulator of the v-ATPase, Forming a Control Module for Cellular Homeostasis With v-ATPase and TORC1

J Cell Sci. 2015 Aug 1;128(15):2938-50. doi: 10.1242/jcs.173807. Epub 2015 Jun 19.

Abstract

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.

Keywords: Gut; MITF; Melanocytes; TFEB; TORC1; v-ATPase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Drosophila
  • Drosophila Proteins / metabolism*
  • Enzyme Activation
  • Homeostasis / physiology
  • Humans
  • Melanocytes / metabolism
  • Melanoma / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • Mitochondrial Proton-Translocating ATPases / genetics
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering
  • Transcription Factors / metabolism*
  • Transcription, Genetic / genetics
  • Vacuolar Proton-Translocating ATPases / genetics*
  • Vacuolar Proton-Translocating ATPases / metabolism

Substances

  • Drosophila Proteins
  • MT-ATP6 protein, human
  • Microphthalmia-Associated Transcription Factor
  • RNA, Small Interfering
  • TORC1 protein complex, Drosophila
  • Transcription Factors
  • Vacuolar Proton-Translocating ATPases
  • Mitochondrial Proton-Translocating ATPases