USP1 deubiquitinates Akt to inhibit PI3K-Akt-FoxO signaling in muscle during prolonged starvation.

EMBO Reports
D. GoldbraikhShenhav Cohen

Abstract

PI3K-Akt-FoxO-mTOR signaling is the central pathway controlling growth and metabolism in all cells. Ubiquitination of the protein kinase Akt prior to its phosphorylation is required for PI3K-Akt activity. Here, we found that the deubiquitinating (DUB) enzyme USP1 removes K63-linked polyubiquitin chains on Akt to restrict PI3K-Akt-FoxO signaling in mouse muscle during prolonged starvation. DUB screening platform identified USP1 as a direct DUB for Akt, and USP1 depletion in mouse muscle increased Akt ubiquitination, PI3K-Akt-FoxO signaling, and glucose uptake during fasting. Co-immunoprecipitation and mass spectrometry identified disabled homolog-2 (Dab2), the tuberous sclerosis complex TSC1/TSC2, and PHLPP1 as USP1 bound proteins. During starvation, Dab2 is essential for Akt recruitment to USP1-TSC1-PHLPP1 complex, and for PI3K-Akt-FoxO inhibition. Surprisingly, USP1 limits TSC1 levels to sustain mTOR-mediated basal protein synthesis rates and maintain its own protein levels. We propose that Dab2 recruits Akt to USP1-TSC1-PHLPP1 complex to efficiently terminate the transmission of growth signals when cellular energy level is low.

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Citations

Oct 3, 2020·Molecular Cancer·Tianshui SunQing Yang
Jan 21, 2021·Biomolecules·Dina Aweida, Shenhav Cohen
Jan 6, 2021·Molecular and Cellular Biology·Agnieszka T KawashimaAlexandra C Newton
Jul 1, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Shenhav Cohen
Jul 3, 2021·International Journal of Molecular Sciences·So-Hee Kim, Kwang-Hyun Baek
Aug 18, 2021·Journal of Chemical Neuroanatomy·Vaibhav OliPravir Kumar
Aug 23, 2021·Journal of Hematology & Oncology·Hui HuaYangfu Jiang
Jul 29, 2021·American Journal of Physiology. Cell Physiology·Jennifer E GildaShenhav Cohen

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