Regulation of Neuroinflammation by Microglial DUBA‐IRAK1‐IKKβ Signaling Loop

Abstract Activation of microglia is closely associated with neuroinflammation. However, the cell‐intrinsic molecular mechanisms translating microglia activation into neuroinflammation are only partially understood. Here, it is shown that deubiquitinating enzyme A (DUBA) is upregulated in microglia under neuroinflammatory conditions in both mice and humans. Mechanistically, activation of microglia induces DUBA self‐deubiquitination and stabilization, leading to the rapid upregulation of DUBA protein levels. In turn, stabilized DUBA increases proinflammatory gene induction in activated microglia by enhancing the activation of nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinase (MAPK) signaling. Of note, DUBA promotes NF‐κB and MAPK activation by stabilizing interleukin‐1 receptor activated kinase 1 (IRAK1) through K48 deubiquitination. Importantly, specific ablation of DUBA in microglia mitigates lipopolysaccharide‐induced depression‐like behavior and ischemic stroke injury in mice by limiting neuroinflammation. Collectively, these findings establish DUBA as a key regulator of microglia in neuroinflammation and uncover novel molecular mechanisms for DUBA in inflammatory signal transduction.