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

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 () and Xiao-Dong Zhang ()
Additional contact information
Shang-Ze Li: Wuhan 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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48288-z

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