title: Mitf is a master regulator of the v-ATPase, forming a control module for cellular homeostasis with v-ATPase and TORC1.
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.
authors.affiliation: Department of Ophthalmology, Center for Vision Research and SUNY Eye Institute, Upstate Medical University, Syracuse, 13210 NY, USA.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Center for Vision Research and SUNY Eye Institute, Upstate Medical University, Syracuse, 13210 NY, USA.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik 101, Iceland.
authors.forename: Margret Helga
authors.initials: MH
authors.lastname: Ogmundsdottir
authors.affiliation: Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik 101, Iceland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Möller
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, OX3 7DQ Oxford, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Siddaway
authors.affiliation: Institut Curie, INSERM U1021, CNRS UMR3347, Normal and Pathological Development of Melanocytes, 91405 Orsay, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
authors.affiliation: Informatics Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsing
authors.affiliation: Informatics Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Sek Won
authors.initials: SW
authors.lastname: Kong
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, OX3 7DQ Oxford, UK.
authors.forename: Colin Ronald
authors.initials: CR
authors.lastname: Goding
authors.affiliation: Life and Environmental Sciences, School of Engineering and Natural Sciences, University of Iceland, Vatnsmyrarvegur 16, Reykjavik 101, Iceland.
authors.forename: Arnar
authors.initials: A
authors.lastname: Palsson
authors.affiliation: Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik 101, Iceland eirikurs@hi.is pignoniF@upstate.edu.
authors.forename: Eirikur
authors.initials: E
authors.lastname: Steingrimsson
authors.affiliation: Department of Ophthalmology, Center for Vision Research and SUNY Eye Institute, Upstate Medical University, Syracuse, 13210 NY, USA Departments of Neuroscience and Physiology, Biochemistry and Molecular Biology, Upstate Medical University, Syracuse, 13210 NY, USA eirikurs@hi.is pignoniF@upstate.edu.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pignoni
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C501005:MT-ATP6 protein, human; D051739:Microphthalmia-Associated Transcription Factor; D034741:RNA, Small Interfering; C570998:TORC1 protein complex, Drosophila; D014157:Transcription Factors; D025262:Vacuolar Proton-Translocating ATPases; D025261:Mitochondrial Proton-Translocating ATPases
keywords: Gut; MITF; Melanocytes; TFEB; TORC1; v-ATPase