Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors

Shengzhe Zhang, Meiying Zhang, Ying Jing, Xia Yin, Pengfei Ma, Zhenfeng Zhang, Xiaojie Wang, Wen Di and Guanglei Zhuang ()
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Shengzhe Zhang: Shanghai Jiao Tong University
Meiying Zhang: Shanghai Jiao Tong University
Ying Jing: Shanghai Jiao Tong University
Xia Yin: Shanghai Jiao Tong University
Pengfei Ma: Shanghai Jiao Tong University
Zhenfeng Zhang: Shanghai Jiao Tong University
Xiaojie Wang: Shanghai Jiao Tong University School of Medicine
Wen Di: Shanghai Jiao Tong University
Guanglei Zhuang: Shanghai Jiao Tong University

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02693-9

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