Mitf is a master regulator of the v-ATPase, forming a control module for cellular homeostasis with v-ATPase and TORC1

T. Zhang, Q. Zhou, Margret H Ogmundsdottir, Katrin Möller, R. Siddaway, L. Larue, M. Hsing, S. W. Kong, C. R. Goding, Arnar Palsson, Eirikur Steingrimsson, F. Pignoni

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)2938-2950
JournalJournal of Cell Science
Volume128
Issue number15
DOIs
Publication statusPublished - 19 Jun 2015

Other keywords

  • MITF
  • TFEB
  • TORC1
  • Gut
  • Melanocytes
  • v-ATPase
  • Ensím
  • Frumulíffræði
  • Gen
  • Meltingarfæri

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