MOF-mediated PRDX1 acetylation regulates LPS-induced macrophage activation.

Macrophages respond to environmental cues in a plastic manner and play a crucial role in host defense, inflammation, and tissue homeostasis. Macrophage activation undergoes metabolic and transcriptomic reprogramming to adapt and tailor an appropriate response, regulating inflammation. Reactive oxygen species (ROS) have been shown to play a pivotal role in macrophage activation. Nevertheless, the detailed molecular mechanism of how initial redox signals direct macrophage activation is not fully elucidated. Here, we uncover an unconventional role for histone acetyltransferase MOF (also known as KAT8) in regulating LPS-induced macrophage activation via modulating the acetylation of peroxiredoxin 1 (PRDX1), an H2O2 scavenger. We demonstrate that PRDX1 is a novel substrate of MOF and identify the major MOF-mediated acetylation site at lysine 197. K197 acetylation of PRDX1 (K197ac PRDX1) is dynamic and reversely regulated by HDAC6 or SIRT2. We observe that this acetylation is readily diminished in the immediate response to LPS. We demonstrate that K197ac PRDX1 fine-tunes its peroxidase activity, leading to the modulation of intracellular ROS levels in early response to LPS stimulation. Moreover, K197ac PRDX1 specifically regulates ERK1/2 phosphorylation, thereby modulating glycolytic metabolism in inflammatory macrophages. Consequently, K197ac PRDX1 tunes the expression and production of the proinflammatory cytokine, IL-6. Taken together, our findings describe a novel signaling module, MOF-PRDX1-ERK, which regulates LPS-induced macrophage activation at the metabolic and transcriptional levels.