Abstract
Ubiquitin-specific protease 14 (USP14) is one of the major proteasome-associated deubiquitinating enzymes critical for proteome homeostasis. However, substrates of USP14 remain largely unknown, hindering the understanding of its functional roles. Here we conduct a comprehensive proteome, ubiquitinome and interactome analysis for USP14 substrate screening. Bioinformatics analysis reveals broad new potential roles of USP14, especially in lipid and carbohydrate metabolism. Among the potential substrates identified, we show that fatty acid synthase (FASN), a key enzyme involved in hepatic lipogenesis, is a bona fide substrate of USP14. USP14 directly interacts with and increases FASN stability. As a result, overexpression of USP14 promotes liver triglyceride accumulation in C57BL/6 mice, whereas genetic ablation or pharmacological inhibition of USP14 ameliorates hepatosteatosis, hyperglycemia and insulin resistance in obese mice. In conclusion, our findings reveal for the first time an indispensable role of USP14 in hepatosteatosis through FASN stabilization.
Highlights
Ubiquitin-specific protease 14 (USP14) is one of the major proteasome-associated deubiquitinating enzymes critical for proteome homeostasis
We previously carried out Affymetrix arrays using livers of mice fed a high-fat diet (HFD) or a normal chow diet (ND)[25,26], and by reanalysis of these data we found that the mRNA levels of several ubiquitin-specific proteases (USPs) family members were significantly upregulated (p < 0.05 by Student's ttest) in HFD mouse livers (Supplementary Fig. 1)
Among these USP members, we found that the expression of USP14 was increased in HFD-fed mice (Supplementary Fig. 1)
Summary
Ubiquitin-specific protease 14 (USP14) is one of the major proteasome-associated deubiquitinating enzymes critical for proteome homeostasis. USP14 was overexpressed in many cancers and promoted tumor cell proliferation through enhancing β-catenin accumulation and inhibiting Bcl-xl-mediated cell apoptosis[11]. These studies have demonstrated the importance of USP14 in cell physiology and diseases, the question of whether USP14 participates in other biological events, especially in energy metabolism, remains largely unexplored. This study identified new possible substrates of USP14, and revealed the broad new cellular pathways that USP14 were highly associated with, especially in lipid and carbohydrate metabolism.
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