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Wdr59 promotes or inhibits TORC1 activity depending on cellular context

Yingbiao Zhang1, Chun-Yuan Ting1, Shu Yang1

  • 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.

Proceedings of the National Academy of Sciences of the United States of America
|December 28, 2022
PubMed

Insights

Wdr59 has a dual role in regulating the Target of Rapamycin Complex I (TORC1) pathway. It can inhibit TORC1 in some tissues by opposing GATOR2, but promote TORC1 activation in others by stabilizing GATOR2 components.

Area of Science:

  • Cellular metabolism
  • Signal transduction pathways
  • Eukaryotic gene regulation

Background:

  • The Target of Rapamycin Complex I (TORC1) pathway is a critical regulator of cellular metabolism and growth in eukaryotes.
  • The GTPase-activating protein toward Rags (GATOR) signaling pathway, comprising GATOR1 and GATOR2 subcomplexes, acts upstream of TORC1.
  • GATOR1 inhibits TORC1 activity during amino acid limitation, while GATOR2 antagonizes GATOR1, thereby promoting TORC1 activation.

Purpose of the Study:

  • To investigate the function of Wdr59, a component initially assigned to the GATOR2 complex, in TORC1 regulation.
  • To elucidate the context-dependent roles of Wdr59 in different cellular environments and organisms.

Main Methods:

  • Utilized *Drosophila* models, specifically examining Wdr59 function in the ovary, eye imaginal disc, and fat body.
  • Employed mammalian HeLa cells to study Wdr59's effect on GATOR2 protein stability and TORC1 activity.
  • Investigated the impact of proteasome inhibition on TORC1 activity and GATOR2 protein levels in Wdr59 knockout cells.

Main Results:

  • In *Drosophila* ovary and eye imaginal disc, Wdr59 inhibits TORC1 by counteracting GATOR2's inhibition of GATOR1.
  • In *Drosophila* fat body and mammalian HeLa cells, Wdr59 promotes GATOR2 stability (Mio and Wdr24) and is essential for TORC1 activation.
  • Wdr59 knockout in HeLa cells leads to reduced GATOR2 levels and diminished TORC1 activity, which is rescued by proteasome inhibition.

Conclusions:

  • Wdr59 exhibits a dual function in TORC1 regulation, acting as an inhibitor or promoter depending on the cellular context.
  • Wdr59's role in GATOR2 complex stability is crucial for context-specific TORC1 pathway modulation.
  • These findings reveal a complex regulatory mechanism for TORC1 signaling involving Wdr59's adaptable function within the GATOR complex.
Keywords:
DrosophilaGATOR1GATOR2TORC1Wdr59

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