Wdr59 promotes or inhibits TORC1 activity depending on cellular context

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.