2. Academic Validation
  3. SET7 methylates the deubiquitinase OTUB1 at Lys 122 to impair its binding to E2 enzyme UBC13 and relieve its suppressive role on ferroptosis

SET7 methylates the deubiquitinase OTUB1 at Lys 122 to impair its binding to E2 enzyme UBC13 and relieve its suppressive role on ferroptosis

  • J Biol Chem. 2023 Feb 21;103054. doi: 10.1016/j.jbc.2023.103054.
Hongyan Deng 1,  Shuke Jia 2,  Jinhua Tang 2,  Fangjing Rong 2,  Chenxi Xu 2,  Xiaoyun Chen 2,  Zixuan Wang 2,  Chunchun Zhu 2,  Xueyi Sun 2,  Qian Liao 2,  Wen Liu 2,  Wenhua Li 3,  Wuhan Xiao 4,  Xing Liu 5
Affiliations

Affiliations

  • 1 College of Life Science, Wuhan University, Wuhan, 430072, P. R. China; State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China.
  • 2 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China; University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
  • 3 College of Life Science, Wuhan University, Wuhan, 430072, P. R. China. Electronic address: [email protected].
  • 4 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China; Hubei Hongshan Laboratory, Wuhan, 430070, P. R. China; University of Chinese Academy of Sciences, Beijing, 100049, P. R. China; The Innovation of Seed Design, Chinese Academy of Sciences, Wuhan, 430072, P. R. China. Electronic address: [email protected].
  • 5 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China; Hubei Hongshan Laboratory, Wuhan, 430070, P. R. China; University of Chinese Academy of Sciences, Beijing, 100049, P. R. China. Electronic address: [email protected].
PMID: 36822329 DOI: 10.1016/j.jbc.2023.103054
Abstract

The deubiquitinating Enzyme OTUB1 possesses canonical Deubiquitinase (DUB) activity and non-canonical, catalytic-independent activity, which has been identified as an essential regulator of diverse physiological processes. Posttranslational modifications of OTUB1 affect both its DUB activity and its non-canonical activity of binding to the E2 ubiquitin-conjugation Enzyme UBC13, but further investigation is needed to characterize the full inventory of modifications to OTUB1. Here, we demonstrate that SET7, a lysine monomethylase, directly interacts with OTUB1 to catalyze OTUB1 methylation at lysine 122. This modification does not affect DUB activity of OTUB1, but impairs its non-canonical activity, binding to UBC13. Moreover, we found using cell viability analysis and intracellular Reactive Oxygen Species (ROS) assay that SET7-mediated methylation of OTUB1 relieves its suppressive role on Ferroptosis. Notably, the methylation mimic mutant of OTUB1 not only loses the ability to bind to UBC13, but also relieves its suppressive role on Tert-Butyl hydroperoxide (TBH)-induced cell death, and Cystine starvation/Erastin-induced cellular ROS. Collectively, our data identify a novel modification of OTUB1 that is critical for inhibiting its non-canonical activity.

Keywords

OTUB1; SET7; UBC13; ferroptosis; methylation.

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