MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination. As a result, USP13 depletion using CRISPR/Cas9 nuclease system inhibits tumor growth in xenografted nude mice. We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL. Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies.

中文翻译：

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去泛素酶USP13决定了MCL1对BH3模拟抑制剂的稳定性和敏感性。

MCL1是抗凋亡BCL-2家族蛋白的关键成员。尽管MCL1的一个显着特征在于其有效的泛素化和破坏作用，但去泛素化酶USP9X已通过去除聚泛素链与MCL1表达的保存有关。在这里，我们进行了无偏见的siRNA筛选，并确定第二个去泛素酶USP13调节肺癌和卵巢癌细胞中MCL1的稳定性。从机理上讲，USP13通过去泛素化与MCL1相互作用并使其稳定。结果，使用CRISPR / Cas9核酸酶系统的USP13耗竭抑制了异种移植裸鼠中的肿瘤生长。我们进一步报告说，USP13的遗传或药理抑制作用大大降低了MCL1蛋白的丰度，并显着提高了肿瘤细胞对靶向BCL-2和BCL-XL的BH3模拟抑制剂的敏感性。总的来说，