Polo like kinase 2 (PLK2) promotes microglial activation via regulation of the HSP90α/IKKβ pathway

Microglial overactivation is actively involved in the pathogenesis of neurodegenerative diseases. Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase associated with the regulation of synaptic plasticity and centriole duplication. Here, we identified PLK2 as an important early response gene in lipopolysaccharide (LPS)-stimulated microglial cells. Knockdown or inhibition of PLK2 remarkably attenuated LPS-induced expression of pro-inflammatory factors such as IL-1β, IL-6, COX2, TNF-α, and iNOS in microglial cells via suppressing the IKKβ-NF-κB signaling pathway. Notably, overexpression of PLK2 induced expression of pro-inflammatory factors and NF-κB transcriptional activation in the absence of inflammatory stimuli. Mechanistically, co-immunoprecipitation experiments revealed association between PLK2 and IKKβ, whereas GST pull-down assay showed no direct interaction between PLK2 and IKKβ. Proteomic analysis and in vitro kinase assay identified heat shock protein 90 alpha (HSP90α), a regulator of IKKβ activity, as a novel PLK2 substrate. Knockdown or pharmacological inhibition of HSP90α abolished PLK2-mediated activation of NF-κB transcriptional activity and microglial inflammatory activation. Furthermore, phosphoproteomic analysis pinpointed Ser252 and Ser263 on HSP90α as novel phosphorylation targets of PLK2. Subsequent functional studies demonstrated that re-expression of phosphor-dead mutation of these two phosphorylation sites on HSP90α failed to rescue the PLK2-induced activation of the NF-κB signaling. Lastly, conditional knockout of PLK2 in microglial cells dramatically ameliorated neuroinflammation and subsequent dopaminergic neuron loss in an intracranial LPS-induced mouse PD model. The present study revealed, for the first time, that PLK2 promoted microglial activation through the phosphorylation of HSP90α and subsequent activation of the IKKβ-NF-κB signaling pathway. Consequently, PLK2 emerges as a potential therapeutic target for the amelioration of neuroinflammation-related diseases.