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Minimal Membrane Interactions Conferred by Rheb C-terminal Farnesylation are Essential for mTORC1 Activation

Brittany Angarola, View ORCID ProfileShawn M. Ferguson
doi: https://doi.org/10.1101/513473
Brittany Angarola
1Departments of Cell Biology and Neuroscience, Yale University School of Medicine, New Haven, CT, 06510
2Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, 06510
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Shawn M. Ferguson
1Departments of Cell Biology and Neuroscience, Yale University School of Medicine, New Haven, CT, 06510
2Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, 06510
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  • ORCID record for Shawn M. Ferguson
  • For correspondence: shawn.ferguson@yale.edu
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Abstract

Stable localization of the Rheb GTPase to lysosomes is thought to be required for activation of mTORC1 signaling. However, the lysosome targeting mechanisms for Rheb remain unclear. We therefore investigated the relationship between Rheb subcellular localization and mTORC1 activation. Surprisingly, we found that although Rheb was prominently enriched at the endoplasmic reticulum (ER), Rheb was undetectable at lysosomes. Functional assays in knockout human cells revealed that farnesylation of the C-terminal CaaX motif on Rheb was essential for both Rheb enrichment on ER membranes and mTORC1 activation. However, constitutively targeting Rheb to ER membranes did not support mTORC1 activation. Further systematic analysis of the Rheb hypervariable region revealed that weak, non-selective, farnesylation-dependent, membrane interactions confer Rheb function without the need for a specific lysosome targeting motif. Collectively, these results argue against stable interactions of Rheb with lysosomes and instead that transient membrane interactions optimally allow Rheb to activate mTORC1 signaling.

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Posted January 08, 2019.
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Minimal Membrane Interactions Conferred by Rheb C-terminal Farnesylation are Essential for mTORC1 Activation
Brittany Angarola, Shawn M. Ferguson
bioRxiv 513473; doi: https://doi.org/10.1101/513473
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Minimal Membrane Interactions Conferred by Rheb C-terminal Farnesylation are Essential for mTORC1 Activation
Brittany Angarola, Shawn M. Ferguson
bioRxiv 513473; doi: https://doi.org/10.1101/513473

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