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
  • 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.
Products