title: WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes.
abstract: The ability to sense energy status is crucial in the regulation of metabolism via the mechanistic Target of Rapamycin Complex 1 (mTORC1). The assembly of the TTT-Pontin/Reptin complex is responsive to changes in energy status. Under energy-sufficient conditions, the TTT-Pontin/Reptin complex promotes mTORC1 dimerization and mTORC1-Rag interaction, which are critical for mTORC1 activation. We show that WAC is a regulator of energy-mediated mTORC1 activity. In a Drosophila screen designed to isolate mutations that cause neuronal dysfunction, we identified wacky, the homolog of WAC. Loss of Wacky leads to neurodegeneration, defective mTOR activity, and increased autophagy. Wacky and WAC have conserved physical interactions with mTOR and its regulators, including Pontin and Reptin, which bind to the TTT complex to regulate energy-dependent activation of mTORC1. WAC promotes the interaction between TTT and Pontin/Reptin in an energy-dependent manner, thereby promoting mTORC1 activity by facilitating mTORC1 dimerization and mTORC1-Rag interaction.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: David-Morrison
authors.affiliation: The Brown Foundation Institute of Molecular Medicine, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: The Brown Foundation Institute of Molecular Medicine, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Yan-Ning
authors.initials: YN
authors.lastname: Rui
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Charng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Jaiswal
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiong
authors.affiliation: Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Sandoval
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lita
authors.initials: L
authors.lastname: Duraine
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: The Brown Foundation Institute of Molecular Medicine, The University of Texas Medical School at Houston, Houston, TX 77030, USA; Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, Houston, TX 77030, USA; Programs in Human and Molecular Genetics and Neuroscience, The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA. Electronic address: sheng.zhang@uth.tmc.edu.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D055503:Protein Multimerization; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; C539695:WAC protein, Drosophila; C486546:rept protein, Drosophila; D058570:TOR Serine-Threonine Kinases; D004265:DNA Helicases; D020559:Monomeric GTP-Binding Proteins; C504804:pont protein, Drosophila
keywords: Drosophila; Wacky; autophagy; energy sensing; neurodegeneration
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