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CLK2 mediates IκBα-independent early termination of NF-κB activation by inducing cytoplasmic redistribution and degradation

Author

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  • Shang-Ze Li

    (Wuhan University
    Chongqing University)

  • Qi-Peng Shu

    (Wuhan University)

  • Hai-Meng Zhou

    (Wuhan University)

  • Yu-Ying Liu

    (Wuhan University)

  • Meng-Qi Fan

    (Wuhan University)

  • Xin-Yi Liang

    (Wuhan University)

  • Lin-Zhi Qi

    (Chongqing University)

  • Ya-Nan He

    (Wuhan University)

  • Xue-Yi Liu

    (Wuhan University)

  • Xue-Hua Du

    (Wuhan University)

  • Xi-Chen Huang

    (Wuhan University)

  • Yu-Zhen Chen

    (Affiliated Hospital of Youjiang Medical University for Nationalities)

  • Run-Lei Du

    (Wuhan University)

  • Yue-Xiu Liang

    (Affiliated Hospital of Youjiang Medical University for Nationalities)

  • Xiao-Dong Zhang

    (Wuhan University
    Affiliated Hospital of Youjiang Medical University for Nationalities
    University of South China)

Abstract

Activation of the NF-κB pathway is strictly regulated to prevent excessive inflammatory and immune responses. In a well-known negative feedback model, IκBα-dependent NF-κB termination is a delayed response pattern in the later stage of activation, and the mechanisms mediating the rapid termination of active NF-κB remain unclear. Here, we showed IκBα-independent rapid termination of nuclear NF-κB mediated by CLK2, which negatively regulated active NF-κB by phosphorylating the RelA/p65 subunit of NF-κB at Ser180 in the nucleus to limit its transcriptional activation through degradation and nuclear export. Depletion of CLK2 increased the production of inflammatory cytokines, reduced viral replication and increased the survival of the mice. Mechanistically, CLK2 phosphorylated RelA/p65 at Ser180 in the nucleus, leading to ubiquitin‒proteasome-mediated degradation and cytoplasmic redistribution. Importantly, a CLK2 inhibitor promoted cytokine production, reduced viral replication, and accelerated murine psoriasis. This study revealed an IκBα-independent mechanism of early-stage termination of NF-κB in which phosphorylated Ser180 RelA/p65 turned off posttranslational modifications associated with transcriptional activation, ultimately resulting in the degradation and nuclear export of RelA/p65 to inhibit excessive inflammatory activation. Our findings showed that the phosphorylation of RelA/p65 at Ser180 in the nucleus inhibits early-stage NF-κB activation, thereby mediating the negative regulation of NF-κB.

Suggested Citation

  • Shang-Ze Li & Qi-Peng Shu & Hai-Meng Zhou & Yu-Ying Liu & Meng-Qi Fan & Xin-Yi Liang & Lin-Zhi Qi & Ya-Nan He & Xue-Yi Liu & Xue-Hua Du & Xi-Chen Huang & Yu-Zhen Chen & Run-Lei Du & Yue-Xiu Liang & Xi, 2024. "CLK2 mediates IκBα-independent early termination of NF-κB activation by inducing cytoplasmic redistribution and degradation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48288-z
    DOI: 10.1038/s41467-024-48288-z
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    References listed on IDEAS

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    1. Lorena Riol-Blanco & Jose Ordovas-Montanes & Mario Perro & Elena Naval & Aude Thiriot & David Alvarez & Silke Paust & John N. Wood & Ulrich H. von Andrian, 2014. "Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation," Nature, Nature, vol. 510(7503), pages 157-161, June.
    2. Shang-Ze Li & Qi-Peng Shu & Yang Song & Hui-Hui Zhang & Yi Liu & Bing-Xue Jin & Tian-Zi Liuyu & Chao Li & Xi-Chen Huang & Run-Lei Du & Wei Song & Bo Zhong & Xiao-Dong Zhang, 2019. "Phosphorylation of MAVS/VISA by Nemo-like kinase (NLK) for degradation regulates the antiviral innate immune response," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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