USP1 deubiquitinates Akt to inhibit PI3K‐Akt‐FoxO signaling in muscle during prolonged starvation. (5th March 2020)

• Record Type: Journal Article
• Authors: Goldbraikh, Dana; Neufeld, Danielle; Eid‐Mutlak, Yara; Lasry, Inbal; Gilda, Jennifer E; Parnis, Anna; Cohen, Shenhav
• Is Part Of: EMBO reports. Volume 21:Number 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-03-05
• Subjects: Dab2 -- fasting -- muscle atrophy -- PI3K‐Akt signaling -- USP1; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201948791
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: The deubiquitinating enzyme USP1 restricts PI3K‐Akt‐FoxO signaling in muscle atrophy by removing K63‐linked polyubiquitin chains on Akt. During fasting, Dab2 promotes the recruitment of Akt to USP1, which together with the phosphatase PHLPP1 inhibits Akt, thereby suppressing PI3K‐Akt signaling when cellular energy level is low. USP1 directly deubiquitinates and inhibits Akt to sustain PI3K‐Akt‐FoxO signaling low in the muscle during prolonged starvation (low insulin condition). During fasting, Dab2 promotes the recruitment of Akt to USP1, which also binds the tuberous sclerosis complex TSC1/TSC2, and the phosphatase PHLPP1. USP1‐mediated deubiquitination of Akt reduces Akt phosphorylation at T308 in fasting, but loss of Akt phosphorylation at S473 requires PHLPP1. To maintain its own protein levels high, USP1 limits TSC1 levels to sustain mTOR‐mediated basal protein synthesis rates in fasting. Abstract : USP1 regulates PI3K‐Akt‐FoxO and mTOR signalling in the muscle during prolonged starvation to maintain homeostasis under low energy conditions.