The deubiquitinase USP11 regulates cell proliferation and ferroptotic cell death via stabilization of NRF2 USP11 deubiquitinates and stabilizes NRF2
The deubiquitinase USP11 regulates cell proliferation and ferroptotic cell death via stabilization of NRF2 USP11 deubiquitinates and stabilizes NRF2
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去泛素酶 USP11 调节细胞增殖去泛素酶 USP11 通过稳定 NRF2 调节细胞增殖和铁死亡细胞 USP11 通过稳定 NRF2 去泛素化并稳定 NRF2 化和铁死亡细胞死亡
DOI：
10.1038/s41388-021-01660-5
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发表时间：
2021-02-02
期刊：
影响因子：
8
通讯作者：
Luo, Jianyuan
中科院分区：
文献类型：
--
作者：
Meng, Chunjie;Zhan, Jun;Luo, Jianyuan
转录因子核因子（红细胞衍生2）样2（NRF 2）在癌症进展中起关键作用，并受到蛋白酶体途径的严格调控。E3连接酶介导的NRF 2泛素化已被广泛报道，但NRF 2去泛素化的机制仍不清楚。在这里，我们鉴定了NRF 2复合物中的泛素特异性加工蛋白酶11（USP 11），并证实了这两种蛋白质之间的相互作用。我们进一步发现USP 11去泛素化NRF 2;这种修饰稳定了NRF 2。在功能上，USP 11耗竭有助于抑制细胞增殖和诱导ROS介导的应激导致的铁凋亡细胞死亡，这可以通过NRF 2的过表达而在很大程度上消除。最后，使用肺组织芯片进行USP 11和NRF 2的免疫组织化学染色，结果显示USP 11在NSCLC患者中高表达，并且与NRF 2表达呈正相关。总之，USP 11稳定NRF 2，因此是细胞增殖和铁凋亡的重要参与者。
The transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays a key role in cancer progression and is tightly regulated by the proteasome pathway. E3 ligases that mediate NRF2 ubiquitination have been widely reported, but the mechanism of NRF2 deubiquitination remains largely unclear. Here, we identified ubiquitin-specific-processing protease 11 (USP11) in NRF2 complexes and confirmed an interaction between these two proteins. We further found that USP11 deubiquitinates NRF2; this modification stabilizes NRF2. Functionally, USP11 depletion contributes to the suppression of cell proliferation and induction of ferroptotic cell death due to ROS-mediated stress, which can be largely abrogated by overexpression of NRF2. Finally, immunohistochemical staining of USP11 and NRF2 was performed using a lung tissue microarray, which revealed that USP11 is highly expressed in patients with NSCLC and positively correlated with NRF2 expression. Together, USP11 stabilizes NRF2 and is thus an important player in cell proliferation and ferroptosis.