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

Activation of the NF-kappa B pathway is strictly regulated to prevent excessive inflammatory and immune responses. In a well-known negative feedback model, I kappa B alpha-dependent NF-kappa B termination is a delayed response pattern in the later stage of activation, and the mechanisms mediating the rapid termination of active NF-kappa B remain unclear. Here, we showed I kappa B alpha-independent rapid termination of nuclear NF-kappa B mediated by CLK2, which negatively regulated active NF-kappa B by phosphorylating the RelA/p65 subunit of NF-kappa B 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 I kappa B alpha-independent mechanism of early-stage termination of NF-kappa B 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-kappa B activation, thereby mediating the negative regulation of NF-kappa B. The NF-kB pathway is strictly regulated to prevent excessive inflammatory and immune responses. Here, Li et al. describe an alternative pathway of negative regulation of p65- driven gene expression.