WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes

Gabriela David-Morrison, Zhen Xu, Yan-Ning Rui, Wu-Lin Charng, Manish Jaiswal, Shinya Yamamoto, Bo Xiong, Ke Zhang, Hector Sandoval, Lita Duraine, Zhongyuan Zuo, Sheng Zhang, Hugo J Bellen

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)139-51
Number of pages13
JournalDevelopmental Cell
Volume36
Issue number2
DOIs
StatePublished - Jan 25 2016

Keywords

  • Animals
  • Autophagy
  • Carrier Proteins
  • DNA Helicases
  • Drosophila Proteins
  • Drosophila melanogaster
  • Monomeric GTP-Binding Proteins
  • Protein Multimerization
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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