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The deubiquitinase USP11 regulates cell proliferation and ferroptotic cell death via stabilization of NRF2 USP11 deubiquitinates and stabilizes NRF2

Abstract

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.

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Fig. 1: Identification of USP11 as a component of the NRF2 protein complexes.
Fig. 2: USP11 regulates the protein level of NRF2.
Fig. 3: USP11 deubiquitinates NRF2 directly.
Fig. 4: USP11 plays a role in regulating cell proliferation and sensitivity to ferroptosis driven by ROS-mediated stress.
Fig. 5: Decreased NRF2 levels mediated by USP11 inactivation promotes ferroptotic sensitivity and prevents cell proliferation of H1299 cells.
Fig. 6: The pathological relevance of USP11 and NRF2 in lung SCC patients.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (81874147, 81671389, 81621063, 81773199). We thank core facility at Peking University Health Science Center for experiment help. We thank members in Wei Gu’s Lab (Columbia University Medical school) for helps to finish the project.

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WG and JL designed the research. CM, JZ, and DC performed the experiments and analyzed data. CM, JZ, and JL drafted the manuscript. HZ and GS modified the manuscript.

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Correspondence to Jianyuan Luo.

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Meng, C., Zhan, J., Chen, D. et al. The deubiquitinase USP11 regulates cell proliferation and ferroptotic cell death via stabilization of NRF2 USP11 deubiquitinates and stabilizes NRF2. Oncogene 40, 1706–1720 (2021). https://doi.org/10.1038/s41388-021-01660-5

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