2. Academic Validation
  3. Methyltransferase SMYD3 impairs hypoxia tolerance by augmenting hypoxia signaling independent of its enzymatic activity

Methyltransferase SMYD3 impairs hypoxia tolerance by augmenting hypoxia signaling independent of its enzymatic activity

  • J Biol Chem. 2022 Oct 20;102633. doi: 10.1016/j.jbc.2022.102633.
Zixuan Wang 1,  Xiaoyun Chen 1,  Sijia Fan 1,  Chunchun Zhu 1,  Hongyan Deng 2,  Jinhua Tang 1,  Xueyi Sun 1,  Shuke Jia 1,  Qian Liao 1,  Wuhan Xiao 3,  Xing Liu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
  • 2 College of Life Science, Wuhan University, Wuhan, 430072, P. R. China.
  • 3 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences; 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; Hubei Hongshan Laboratory, Wuhan, 430070, P. R. China. Electronic address: w-xiao@ihb.ac.cn.
  • 4 State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences; 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: liuxing@ihb.ac.cn.
PMID: 36273580 DOI: 10.1016/j.jbc.2022.102633
Abstract

HIF1α, a main transcriptional regulator of the cellular response to hypoxia, also plays important roles in oxygen homeostasis of aerobic organisms, which is regulated by multiple mechanisms. However, the full cellular response to hypoxia has not been elucidated. In this study, we found that expression of SMYD3, a methyltransferase, augments hypoxia signaling independent of its enzymatic activity. We demonstrated SMYD3 binds to and stabilizes HIF1α via co-immunoprecipitation and Western blot assays, leading to the enhancement of HIF1α transcriptional activity under hypoxia conditions. In addition, the stabilization of HIF1α by SMYD3 is independent of HIF1α hydroxylation by prolyl hydroxylases (PHDs) and the intactness of the von Hippel-Lindau (VHL) ubiquitin ligase complex. Furthermore, we showed SMYD3 induces ROS accumulation and promotes hypoxia-induced cell Apoptosis. Consistent with these results, we found smyd3-null zebrafish exhibit higher hypoxia tolerance compared to their wildtype siblings. Together, these findings define a novel role of SMYD3 in affecting hypoxia signaling and demonstrate that SMYD3-mediated HIF1α stabilization augments hypoxia signaling, leading to the impairment of hypoxia tolerance.

Keywords

HIF1α; ROS; SMYD3; hypoxia signaling; hypoxia tolerance; zebrafish.

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