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Published on: May 4, 2013
Mitf is a master regulator of the v-ATPase, forming a control module for cellular homeostasis with v-ATPase and TORC1
Tianyi Zhang1, Qingxiang Zhou1, Margret Helga Ogmundsdottir2
1Department of Ophthalmology, Center for Vision Research and SUNY Eye Institute, Upstate Medical University, Syracuse, 13210 NY, USA.
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.
Insights
The transcription factor Mitf masterfully regulates the vacuolar-type proton ATPase (v-ATPase), impacting cellular homeostasis and metabolism. This discovery reveals a conserved regulatory loop involving Mitf, v-ATPase, and TORC1 in both flies and mammals.
Area of Science:
- Cell Biology
- Molecular Biology
- Metabolism
Background:
- Vacuolar-type proton ATPase (v-ATPase) is crucial for cellular homeostasis.
- Mechanisms regulating v-ATPase activity are not fully understood.
- TORC1 is a key metabolic regulator influenced by v-ATPase.
Purpose of the Study:
- To identify master regulators of v-ATPase holoenzyme activity.
- To elucidate the regulatory mechanisms controlling v-ATPase.
- To investigate the interplay between Mitf, v-ATPase, and TORC1.
Main Methods:
- Drosophila melanogaster as a model organism.
- Analysis of transcription factor Mitf's role.
- Investigating cis-regulatory elements (M-box) in v-ATPase genes.
- Assessing TORC1 activity and its feedback on Mitf.
Main Results:
- Mitf directly controls the transcription of all 15 v-ATPase components.
- Mitf-mediated v-ATPase regulation impacts holoenzyme activity in vivo.
- Mitf, v-ATPase, and TORC1 form a negative feedback loop.
- Mechanistic conservation of Mitf-v-ATPase regulation observed in mammalian melanocytic cells.
Conclusions:
- Mitf is a master regulator of the v-ATPase holoenzyme.
- A conserved ancient module of Mitf, v-ATPase, and TORC1 dynamically modulates metabolism.
- This regulatory network maintains cellular homeostasis and metabolic balance.
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