Regulation of Neuroinflammation by Microglial DUBA‐IRAK1‐IKKβ Signaling Loop
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.
Authors
- Yanqi Xu
- Yiting Lu (ORCID: https://orcid.org/0000-0003-4335-3343)
- Kate Lykke Lambertsen (ORCID: https://orcid.org/0000-0001-9276-4902)
- Bincheng Zhou
- Huiyuan Bai (ORCID: https://orcid.org/0009-0008-6944-7464)
- Xian Su (ORCID: https://orcid.org/0000-0002-8295-876X)
- Bettina Hjelm Clausen (ORCID: https://orcid.org/0000-0003-3302-2022)
- Zhongding Li
- Dirk Schlüter (ORCID: https://orcid.org/0000-0003-1478-3328)
- Keke Jin (ORCID: https://orcid.org/0000-0002-6020-318X)
- Weihong Song (ORCID: https://orcid.org/0000-0001-9928-889X)
- Meng Chen (ORCID: https://orcid.org/0000-0002-2449-5904)
- Xu Wang (ORCID: https://orcid.org/0000-0001-8428-9339)
- Ran Li (ORCID: https://orcid.org/0000-0001-6473-4570)
- Yuhua Li (ORCID: https://orcid.org/0000-0002-0982-6680)
- Xiang Cai
- Chaoqun Wang (ORCID: https://orcid.org/0000-0003-0415-6080)
- Baohua Liu (ORCID: https://orcid.org/0000-0002-1599-8059)
- Zi-Jun Cao
- Fuqi Mei
- Xue Du (ORCID: https://orcid.org/0000-0001-9817-6888)
- Kangmin Chen
- Zhenhu Zhu
Institutions
- University of Southern Denmark (DK)
- Wenzhou Medical University (CN)
- Odense University Hospital (DK)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- Medizinische Hochschule Hannover (DE)
- Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University (CN)
- Zhejiang Lab (CN)
- Northeast Forestry University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-08-04
- DOI
- https://doi.org/10.1002/advs.202503972
- Citations
- 1
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.84
Funders
- National Natural Science Foundation of China
- Odense Universitetshospital
- Natural Science Foundation of Zhejiang Province