2. Academic Validation
  3. Regulation of Neuroinflammation by Microglial DUBA-IRAK1-IKKβ Signaling Loop

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

  • Adv Sci (Weinh). 2025 Aug 4:e03972. doi: 10.1002/advs.202503972.
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

Affiliations

  • 1 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
  • 2 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325000, China.
  • 3 Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, 5230, Denmark.
  • 4 BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, 5230, Denmark.
  • 5 Department of Neurology, Odense University Hospital, Odense, 5000, Denmark.
  • 6 Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
  • 7 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.
  • 8 College of Life Sciences, Northeast Forestry University, Harbin, 150040, China.
  • 9 Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany.
PMID: 40755418 DOI: 10.1002/advs.202503972
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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