DataVXAdvanced SciencePaper
journal article·2025-10Open access

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

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

Advanced Science· Volume 12· Issue 40
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Abstract

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.
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Research context

OpenAlex topics: Neuroinflammation and Neurodegeneration Mechanisms · interferon and immune responses · Immune cells in cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

School of Pharmaceutical Sciences Wenzhou Medical University Wenzhou 325035 China

Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health) Wenzhou 325000 China

Department of Neurobiology Research Institute of Molecular Medicine University of Southern Denmark Odense 5230 Denmark

BRIDGE ‐ Brain Research – Inter Disciplinary Guided Excellence Department of Clinical Research University of Southern Denmark Odense 5230 Denmark

Department of Neurology Odense University Hospital Odense 5000 Denmark

Department of Neurological Rehabilitation The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325027 China

Key Laboratory of Alzheimer's Disease of Zhejiang Province Zhejiang Provincial Clinical Research for Mental Disorders Center for Geriatric Medicine and Institute of Aging The First‐affiliated Hospital Wenzhou Medical University Wenzhou Zhejiang 325035 China

College of Life Sciences Northeast Forestry University Harbin 150040 China

Institute of Medical Microbiology and Hospital Epidemiology Hannover Medical School 30625 Hannover Germany

Funding

Natural Science Foundation of Zhejiang Province · National Natural Science Foundation of China

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