2. Academic Validation
  3. UBE2O-mediated monoubiquitination licenses NLRP6 inflammasome activation in the intestine

UBE2O-mediated monoubiquitination licenses NLRP6 inflammasome activation in the intestine

  • Cell Host Microbe. 2026 Jan 14;34(1):86-102.e8. doi: 10.1016/j.chom.2025.12.009.
Decai Wang 1,  Xuequn Chen 1,  Kaiwen Sui 1,  Anlei Wang 1,  Runzhi Li 1,  Weijun Zhou 2,  Xiaoyu Zhu 3,  Yan Hua 4,  Shuanghu Yuan 5,  Rongbin Zhou 1,  Fangyi Dong 6,  Kankan Wang 7,  Jie Zheng 8,  Shu Zhu 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.
  • 2 Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
  • 3 Department of Hematology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 4 Department of Laboratory Medicine, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 5 Department of Radiation Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 6 Department of Hematology, State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 7 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 8 Shanghai Institute of Virology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 9 State Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Department of Digestive Disease, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Electronic address: [email protected].
PMID: 41500221 DOI: 10.1016/j.chom.2025.12.009
Abstract

The NLRP6 inflammasome in intestinal epithelial cells (IECs) is a key sentinel of enteric pathogens, yet its activation mechanism remains enigmatic. Here, we identify monoubiquitination as a critical post-translational switch for NLRP6 inflammasome activation. We demonstrate that the E3 Ligase UBE2O catalyzes dual-site monoubiquitination of NLRP6: at K680-687 to drive oligomerization via a conformational change, and at K115/130 within the nuclear localization signal to enforce cytoplasmic sequestration through steric hindrance. Mice harboring UBE2O deficiency or monoubiquitination-resistant NLRP6 mutations exhibit defective inflammasome activation and heightened susceptibility to rotavirus and Citrobacter rodentium Infection. Furthermore, the UBE2O inhibitor arsenic trioxide suppresses NLRP6-dependent interleukin (IL)-18 secretion in acute promyelocytic leukemia (APL) patients. Thus, UBE2O-mediated dual-site monoubiquitination emerges as a central mechanism licensing NLRP6 inflammasome activation, revealing a new target for modulating intestinal immunity.

Keywords

NLRP6; UBE2O; conformational transition; cytoplasmic sequestration; infection; inflammasome; inflammation; monoubiquitination; oligomerization; steric hindrance.

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