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. 2025 Aug 4:e03972.
doi: 10.1002/advs.202503972. Online ahead of print.

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

Zhenhu Zhu  1   2 , Zhongding Li  1   2 , Kate Lykke Lambertsen  3   4   5 , Zijun Cao  1   2 , Meng Chen  6 , Yanqi Xu  1   2 , Bettina Hjelm Clausen  3   4 , Keshuo Jin  1   2 , Yiting Lu  1 , Fuqi Mei  1   2 , Xue Du  2 , Kangmin Chen  2 , Huiyuan Bai  2 , Xian Su  2 , Bincheng Zhou  1   2 , Baohua Liu  6 , Ran Li  2   7 , Chaoqun Wang  2   7 , Yuhua Li  8 , Xiang Cai  2 , Dirk Schlüter  9 , Weihong Song  2   7 , Xu Wang  1   2   7
Affiliations

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

Zhenhu Zhu et al. Adv Sci (Weinh). .

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.

Keywords: DUBA; microglia; neuroinflammation; signal transduction; ubiquitination.

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