The acetyltransferase GCN5 contributes to neuroinflammation in mice by acetylating and activating the NF-κB subunit p65 in microglia.

Abstract

Neuroinflammation promotes the progression of various neurological and neurodegenerative diseases. Disrupted homeostasis of protein acetylation is implicated in neurodegeneration, and the lysine acetyltransferase GCN5 (also known as KAT2A) is implicated in peripheral inflammation. Here, we investigated whether GCN5 plays a role in neuroinflammation in the brain. Systemic administration of the bacterial molecule LPS in mice to induce peripheral inflammation increased the abundance of GCN5 in various organs, including in the brain and specifically in microglia. In response to LPS, GCN5 mediated the induction of the proinflammatory cytokines TNF-α and IL-6 and the inflammatory mediators COX-2 and iNOS in microglia. Further investigation in cultured microglial cells revealed that GCN5 was activated downstream of the innate immune receptor TLR4 to acetylate Lys³¹⁰ in the NF-κB subunit p65, thereby enabling the nuclear translocation and transcriptional activity of NF-κB and the resulting inflammatory response. Thus, targeting GCN5 might be explored further as a strategy to reduce neuroinflammation in the treatment of associated diseases.