Location-specific inhibition of Akt reveals regulation of mTORC1 activity in the nucleus

Xin Zhou, Yanghao Zhong, Olivia Molinar-Inglis, Maya T. Kunkel, Mingyuan Chen, Tengqian Sun, Jiao Zhang, John Y.-J. Shyy, JoAnn Trejo, Alexandra C. Newton and Jin Zhang ()
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Xin Zhou: University of California, San Diego
Yanghao Zhong: University of California, San Diego
Olivia Molinar-Inglis: University of California, San Diego
Maya T. Kunkel: University of California, San Diego
Mingyuan Chen: University of California, San Diego
Tengqian Sun: University of California, San Diego
Jiao Zhang: University of California San Diego
John Y.-J. Shyy: University of California San Diego
JoAnn Trejo: University of California, San Diego
Alexandra C. Newton: University of California, San Diego
Jin Zhang: University of California, San Diego

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth, nutrient and energy status cues to control cell growth and metabolism. While mTORC1 activation at the lysosome is well characterized, it is not clear how this complex is regulated at other subcellular locations. Here, we combine location-selective kinase inhibition, live-cell imaging and biochemical assays to probe the regulation of growth factor-induced mTORC1 activity in the nucleus. Using a nuclear targeted Akt Substrate-based Tandem Occupancy Peptide Sponge (Akt-STOPS) that we developed for specific inhibition of Akt, a critical upstream kinase, we show that growth factor-stimulated nuclear mTORC1 activity requires nuclear Akt activity. Further mechanistic dissection suggests that nuclear Akt activity mediates growth factor-induced nuclear translocation of Raptor, a regulatory scaffolding component in mTORC1, and localization of Raptor to the nucleus results in nuclear mTORC1 activity in the absence of growth factor stimulation. Taken together, these results reveal a mode of regulation of mTORC1 that is distinct from its lysosomal activation, which controls mTORC1 activity in the nuclear compartment.

Date: 2020
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DOI: 10.1038/s41467-020-19937-w

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