USP 1 deubiquitinates Akt to inhibit PI 3K‐Akt‐FoxO signaling in muscle during prolonged starvation

PI 3K‐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 PI 3K‐Akt activity. Here, we found that the deubiquitinating ( DUB ) enzyme USP 1 removes K63‐linked polyubiquitin chains on Akt to restrict PI 3K‐Akt‐FoxO signaling in mouse muscle during prolonged starvation. DUB screening platform identified USP 1 as a direct DUB for Akt, and USP 1 depletion in mouse muscle increased Akt ubiquitination, PI 3K‐Akt‐FoxO signaling, and glucose uptake during fasting. Co‐immunoprecipitation and mass spectrometry identified disabled homolog‐2 (Dab2), the tuberous sclerosis complex TSC 1/ TSC 2, and PHLPP 1 as USP 1 bound proteins. During starvation, Dab2 is essential for Akt recruitment to USP 1‐ TSC 1‐ PHLPP 1 complex, and for PI 3K‐Akt‐FoxO inhibition. Surprisingly, USP 1 limits TSC 1 levels to sustain mTOR ‐mediated basal protein synthesis rates and maintain its own protein levels. We propose that Dab2 recruits Akt to USP 1‐ TSC 1‐ PHLPP 1 complex to efficiently terminate the transmission of growth signals when cellular energy level is low.