Ubiquitin specific protease18 (USP18), previously known as UBP43, is the Interferon-Stimulated Gene 15 (ISG15) deconjugase. USP18 removes ISG15 from substrate proteins. This study reports that USP18 null mice (versus wild-type mice) exhibited lower lipolysis rates, altered fat to body weight ratios and cold sensitivity. USP18 is a regulator of lipid and fatty acid metabolism. Prior work established that USP18 promotes lung tumorigenesis. We sought to learn if this occurs through altered lipid and fatty acid metabolism. Loss of USP18 repressed adipose triglyceride lipase (ATGL) expression; gain of USP18 expression upregulated ATGL in lung cancer cells. The E1-like ubiquitin activating enzyme (UBE1L) promoted ISG15-conjugation of ATGL and destabilization. Immunoprecipitation assays confirmed that ISG15 covalently conjugates to ATGL. Protein expression of thermogenic regulators was examined in brown fat of USP18 null versus wild-type mice. Uncoupling Protein 1 (UCP1) was repressed in USP18 null fat. Gain of USP18 expression augmented UCP1 protein via reduced ubiquitination. Gain of UCP1 expression in lung cancer cell lines enhanced cellular proliferation. UCP1 knock-down inhibited proliferation. Beta-hydroxybutyrate colorimetric assays performed after gain of UCP1 expression revealed increased cellular fatty acid beta-oxidation, augmenting fatty acid beta-oxidation in seahorse assays. Combined USP18, ATGL and UCP1 profiles were interrogated in The Cancer Genome Atlas (TCGA). Intriguingly, lung cancers with increased USP18, ATGL and UCP1 expression had an unfavorable survival. These findings reveal that USP18 is a pharmacologic target that controls fatty acid metabolism. Implications: USP18 is an antineoplastic target that affects lung cancer fatty acid metabolism.

中文翻译：

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泛素特异性蛋白酶 USP18 促进脂肪分解、脂肪酸氧化和肺癌生长

泛素特异性蛋白酶 18 (USP18)，以前称为 UBP43，是干扰素刺激基因 15 (ISG15) 解偶联酶。USP18 从底物蛋白中去除 ISG15。该研究报告称，USP18 缺失小鼠（与野生型小鼠相比）表现出较低的脂肪分解率、改变的脂肪与体重比率和冷敏感性。USP18 是脂质和脂肪酸代谢的调节剂。先前的工作确定 USP18 促进肺肿瘤发生。我们试图了解这是否通过改变脂质和脂肪酸代谢而发生。USP18 抑制脂肪甘油三酯脂肪酶 (ATGL) 表达的缺失；USP18 表达的增加上调了肺癌细胞中的 ATGL。E1 样泛素激活酶 (UBE1L) 促进了 ATGL 的 ISG15 结合和去稳定化。免疫沉淀测定证实 ISG15 与 ATGL 共价结合。在 USP18 null 与野生型小鼠的棕色脂肪中检查产热调节剂的蛋白质表达。解偶联蛋白 1 (UCP1) 在 USP18 无效脂肪中受到抑制。USP18 表达的增加通过减少泛素化增加了 UCP1 蛋白。肺癌细胞系中UCP1表达的增加增强了细胞增殖。UCP1 敲低抑制增殖。在获得 UCP1 表达后进行的 β-羟基丁酸比色测定显示细胞脂肪酸 β-氧化增加，从而增加了海马测定中的脂肪酸 β-氧化。结合 USP18、ATGL 和 UCP1 谱在癌症基因组图谱 (TCGA) 中进行了询问。有趣的是，USP18、ATGL 和 UCP1 表达增加的肺癌存活率不高。这些发现表明，USP18 是一种控制脂肪酸代谢的药理学靶点。