2. Academic Validation
  3. DUBA sustains the stability of NOD2 and RIPK2 to enhance innate immune responses

DUBA sustains the stability of NOD2 and RIPK2 to enhance innate immune responses

  • Cell Death Differ. 2025 Apr 16. doi: 10.1038/s41418-025-01516-5.
Bincheng Zhou 1 2,  Maojin Yin 1 2,  Xian Su 2 3,  Suhui Sheng 1,  Xue Du 2,  Jiangyun Shen 2,  Kangmin Chen 2,  Deqi Wang 4,  Zhenhu Zhu 2,  Yanqi Xu 1 2,  Zhongding Li 2,  Jianmin Li 5,  Yuhua Li 6,  Jing Ruan 7,  Xu Wang 8 9
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 Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 4 The First School of Medicine and School of Information and Engineering, Wenzhou Medical University, Wenzhou, 325035, China.
  • 5 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 6 College of Life Sciences, Northeast Forestry University, Harbin, 150040, China.
  • 7 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. ruanjing850617@163.com.
  • 8 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. sunrim@163.com.
  • 9 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325000, China. sunrim@163.com.
PMID: 40240520 DOI: 10.1038/s41418-025-01516-5
Abstract

Nucleotide-binding oligomerization domain containing 2 (NOD2) detects conserved fragments of Bacterial peptidoglycan in the cytosol and induces innate immune responses. Here, we found that the NOD2 signaling pathway was critically regulated by the deubiquitinating enzyme DUBA. DUBA-deficient macrophages were defective in NOD2 signaling and produced significantly lower amounts of cytokines and chemokines in response to muramyl dipeptide (MDP). DUBA potentiated NOD2-mediated signal transduction by maintaining the protein levels of NOD2 and receptor-interacting protein kinase 2 (RIPK2). Mechanistically, DUBA interacted with NOD2 and RIPK2 and removed K48-linked polyubiquitin chains from them through enzymatic activity, thereby inhibiting the proteasomal degradation of NOD2 and RIPK2. Macrophage-specific ablation of DUBA attenuated MDP-induced systematic inflammation and liver injury in mice. In addition, DUBA deficiency in macrophages rendered mice hypersensitive to DSS-induced colitis and eliminated the protective effect of MDP treatment in colitis. Thus, DUBA acts as an important regulator of NOD2-mediated signaling and innate immune responses.

Figures
Products
Inhibitors & Agonists