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Deubiquitylating Enzyme OTUB1 Facilitates Neuronal Survival After Intracerebral Hemorrhage Via Inhibiting NF-κB-triggered Apoptotic Cascades

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Abstract

The deubiquitylase OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) has been implicated in the pathogenesis of various human diseases. However, the molecular mechanism by which OTUB1 participates in the pathogenesis of intracerebral hemorrhage (ICH) remains elusive. In the present study, we established an autologous whole blood fusion-induced ICH model in C57BL/6 J mice. We showed that the upregulation of OTUB1 contributes to the attenuation of Nuclear factor kappa B (NF-κB) and its downstream apoptotic signaling after ICH. OTUB1 directly associates with NF-κB precursors p105 and p100 after ICH, leading to attenuated polyubiquitylation of p105 and p100. Moreover, we revealed that NF-κB signaling was modestly activated both in ICH tissues and hemin-exposed HT-22 neuronal cells, accompanied with the activation of NF-κB downstream pro-apoptotic signaling. Notably, overexpression of OTUB1 strongly inhibited hemin-induced NF-κB activation, whereas interference of OTUB1 led to the opposite effect. Finally, we revealed that lentiviral transduction of OTUB1 markedly ameliorated hemin-induced apoptotic signaling and HT-22 neuronal death. Collectively, these findings suggest that the upregulation of OTUB1 serves as a neuroprotective mechanism in antagonizing neuroinflammation-induced NF-κB signaling and neuronal death, shed new light on manipulating intracellular deubiquitylating pathways as novel interventive approaches against ICH-induced secondary neuronal damage and death.

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Data Availability

The data supporting the findings of this study are available from the corresponding author upon request.

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Funding

This work was supported by the National Natural Science Foundation of China (81901195; 81873742).

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  1. Jiabing Shen and Xiaoli Xue contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Affiliated Hospital and Medical School of Nantong University, Nantong, 226001, People’s Republic of China

    Jiabing Shen, Xiaoli Xue, Huimin Yuan, Yan Song, Jinglei Wang, Ronghui Cui & Kaifu Ke

  2. Department of Neurology, Qidong People’s Hospital, Qidong, Jiangsu, People’s Republic of China

    Xiaoli Xue & Huimin Yuan

  3. Department of Neurology, Affiliated Hai’an Hospital of Nantong University and Hai’an People’s Hospital, Hai’an, People’s Republic of China

    Jinglei Wang

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  1. Jiabing Shen
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Contributions

Conceptualization, J. S., R. C. and K. K.; methodology, J. S., X. X. and H. Y.; formal analysis, J. S. and X. X.; investigation, J. S., X. X. and K. K.; resources, J. S., H. Y., Y. S. and J. W.; data curation, J. S., X. X. and K. K.; writing—original draft preparation, J. S., X. X. and H. Y.; writing—review and editing, R. C. and K. K.; visualization, J. S., X. X. and Y. S.; supervision, R. C. and K. K.; project administration, R. C. and K. K.; funding acquisition, R. C. and K. K. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Ronghui Cui or Kaifu Ke.

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The experimental procedures were conducted in accordance with the National Institutes of Health (NIH) laboratory animal care and use guidelines, and have been approved by the Animal Ethics Committee of Nantong University (ethics number: S20180816-012).

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Shen, J., Xue, X., Yuan, H. et al. Deubiquitylating Enzyme OTUB1 Facilitates Neuronal Survival After Intracerebral Hemorrhage Via Inhibiting NF-κB-triggered Apoptotic Cascades. Mol Neurobiol 61, 1726–1736 (2024). https://doi.org/10.1007/s12035-023-03676-2

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