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.

中文翻译：

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USP1 去泛素化 Akt 以抑制长期饥饿期间肌肉中的 PI3K-Akt-FoxO 信号传导

PI3K-Akt-FoxO-mTOR 信号传导是控制所有细胞生长和代谢的中心途径。PI3K-Akt 活性需要蛋白激酶 Akt 在磷酸化之前进行泛素化。在这里，我们发现去泛素化 (DUB) 酶 USP1 去除 Akt 上的 K63 连接的多聚泛素链，以限制长期饥饿期间小鼠肌肉中的 PI3K-Akt-FoxO 信号传导。DUB 筛选平台确定 USP1 是 Akt 的直接 DUB，小鼠肌肉中 USP1 的消耗增加了 Akt 泛素化、PI3K-Akt-FoxO 信号传导以及禁食期间的葡萄糖摄取。免疫共沉淀和质谱鉴定出禁用同源物 2 (Dab2)、结节性硬化症复合物 TSC1/TSC2 和 PHLPP1 为 USP1 结合蛋白。饥饿期间，Dab2 对于 Akt 募集至 USP1-TSC1-PHLPP1 复合物以及 PI3K-Akt-FoxO 抑制至关重要。令人惊讶的是，USP1 限制 TSC1 水平以维持 mTOR 介导的基础蛋白合成率并维持其自身的蛋白水平。我们建议 Dab2 将 Akt 招募到 USP1-TSC1-PHLPP1 复合物中，以在细胞能量水平较低时有效终止生长信号的传递。