RIOK2 kinase regulates the translocation of the FADD-RIPK1-Caspase-8 complex to the ER and the cleavage of Gasdermin D to drive pyroptosis

  • Nat Commun. 2025 Nov 17;16(1):10060. doi: 10.1038/s41467-025-65012-7.
Mingtong Ma  #  1  2 ,  Fei Wang  #  1  2 ,  Pengfei Cui  #  1  2 ,  Yingying Zhang  #  3 ,  Hanyu Ma  1  2 ,  Yifan He  1  2 ,  Yuanna Cheng  1  2 ,  Jingping Huang  1  2 ,  Jingxiang Wang  1  2 ,  Xiangyang Wu  1 ,  Hua Yang  1  2 ,  Ruijuan Zheng  1  2 ,  Haowen Ma  4 ,  Qian Cai  4 ,  Lin Wang  5  6 ,  Baoxue Ge  7  8  9
Affiliations
  • 1. Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2. Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China.
  • 3. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 4. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, College of Pharmacy, Jinan University, Guangzhou, China.
  • 5. Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
  • 6. Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China. [email protected].
  • 7. Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
  • 8. Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China. [email protected].
  • 9. Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41249793 DOI: 10.1038/s41467-025-65012-7
Abstract

Macrophage Infection by the pathogenic bacteria Yersinia or mimic stimulation of lipopolysaccharide (LPS) and transforming growth factor-β-activated kinase 1 (TAK1) inhibitor or tumor necrosis factor (TNF) and TAK1 inhibitor induces caspase-8-mediated gasdermin D (GSDMD) cleavage and Pyroptosis. However, the upstream regulator of caspase-8-dependent cleavage of GSDMD remains elusive. Here we show that Serine/threonine-protein kinase RIO2 (RIOK2) interacts with the Fas-associated protein with death domain (FADD) and is essential for caspase-8-driven GSDMD cleavage. RIOK2's kinase activity drives the transport of lysosome to ER through activating Myosin II and thereby translocate FADD-RIPK1-caspase-8 complex from lysosome to ER. Importantly, RIOK2's ATPase activity enhances its binding to this complex and directly triggers Caspase-8 and gasdermin D cleavage both at ER and in vitro. Furthermore, RIOK2-mediated Pyroptosis enhances host defense against Yersinia Infection. Thus, our findings define an upstream regulator of caspase-8-dependent Pyroptosis, implying a role of organelle crosstalk in spatial cleavage of gasdermins.

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