Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, 200241, China; Department of Molecular and Cellular Biology, Department of Medicine, The Dan L. Duncan Cancer Center, The Diabetes Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cell Metab. 2013 Sep 3;18(3):380-91. doi: 10.1016/j.cmet.2013.08.012.
The ubiquitin-proteasome and autophagy-lysosome systems are major proteolytic pathways, whereas function of the Ub-independent proteasome pathway is yet to be clarified. Here, we investigated roles of the Ub-independent REGγ-proteasome proteolytic system in regulating metabolism. We demonstrate that mice deficient for the proteasome activator REGγ exhibit dramatic autophagy induction and are protected against high-fat diet (HFD)-induced liver steatosis through autophagy. Molecularly, prevention of steatosis in the absence of REGγ entails elevated SirT1, a deacetylase regulating autophagy and metabolism. REGγ physically binds to SirT1, promotes its Ub-independent degradation, and inhibits its activity to deacetylate autophagy-related proteins, thereby inhibiting autophagy under normal conditions. Moreover, REGγ and SirT1 dissociate from each other through a phosphorylation-dependent mechanism under energy-deprived conditions, unleashing SirT1 to stimulate autophagy. These observations provide a function of the REGγ proteasome in autophagy and hepatosteatosis, underscoring mechanistically a crosstalk between the proteasome and autophagy degradation system in the regulation of lipid homeostasis.
泛素-蛋白酶体系统和自噬溶酶体系统是主要的蛋白水解途径，而泛素非依赖性蛋白酶体途径的功能尚未阐明。在这里，我们研究了泛素非依赖性 REGγ-蛋白酶体蛋白水解系统在调节代谢中的作用。我们证明，缺乏蛋白酶体激活剂 REGγ 的小鼠表现出明显的自噬诱导，并通过自噬防止高脂肪饮食 (HFD) 诱导的肝脂肪变性。从分子水平上讲，在没有 REGγ 的情况下防止脂肪变性需要上调 SirT1，这是一种调节自噬和代谢的去乙酰化酶。REGγ 与 SirT1 物理结合，促进其泛素非依赖性降解，并抑制其去乙酰化自噬相关蛋白的活性，从而在正常情况下抑制自噬。此外，在能量匮乏的情况下，通过磷酸化依赖性机制，REGγ 和 SirT1 彼此分离，释放 SirT1 来刺激自噬。这些观察结果为 REGγ 蛋白酶体在自噬和肝脂肪变性中的功能提供了依据，从机制上强调了蛋白酶体和自噬降解系统在调节脂质稳态中的相互作用。
