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Genetic Analysis of TOR Complex 2 Signaling

  • Author(s): Jones, Kevin Theodore
  • Advisor(s): Ashrafi, Kaveh
  • et al.
Abstract

Lipid metabolism is regulated by a complex network of genes spanning numerous biological processes and coordinated functions of multiple tissues. We have established Caenorhabditis elegans as a useful model system to dissect these complex genetic interactions. Our studies have focused mainly on determining the mechanisms by which the TOR (target of rapamycin) complex 2 (TORC2) regulates fat storage, cell size, development, and lifespan. Through genetic analysis of Rictor mutants, we have found that TORC2 signals through activation of sgk-1, not through akt-1/2 or inhibition of daf-16/FOXO, to regulate all of these processes. We have established this relationship through analyzing an existing, amorphic allele of sgk-1 and our isolation of a novel, hypermorphic allele in a forward mutagenesis screen for suppressors of Rictor. We present the initial description of more uncloned suppressors that emerged from this screen. We also present further characterization, both genetic and biochemical, of the phenotypes of Rictor mutants. We further demonstrate that the TORC2-SGK signaling axis is conserved in mammals and plays a physiologically relevant role in the maintenance of blood pressure and salt homeostasis. Finally, we describe several other lines of research aimed at understanding lipid metabolism and stress responses. Through collaborative efforts, we present a description of a novel, mitochondrial stress resistance pathway. We also describe models for studying xenobiotic clearance and the maintenance of lipid homeostasis through sterol response element binding protein (SREBP) signaling. In total, these works yield important insights into TORC2 signaling and, more broadly, help establish C. elegans as a valuable model system for elucidating the regulatory pathways essential for proper lipid storage and metabolism.

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