RNA helicase DDX6 governs ASC speck formation in P-bodies and the transition to stress granules via phase separation during inflammasome activation

  • Cell Discov. 2026 Jun 24;12(1):44. doi: 10.1038/s41421-026-00898-1.
Rudi Mao  #  1  2 ,  Yingqiao Liu  #  1 ,  Zhenyu Fan  1 ,  Yanfeng Li  1 ,  Luyu Yang  1 ,  Qingqing Xie  1 ,  Hong-Peng Dong  1 ,  Mingjun Bi  1 ,  Chengjiang Gao  3 ,  Zhe Yang  4 ,  Tao Xu  5 ,  Xiaopeng Qi  6  7
Affiliations
  • 1. Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 2. Department of Radiation Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 3. Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
  • 4. Department of Radiation Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. [email protected].
  • 5. Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. [email protected].
  • 6. Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. [email protected].
  • 7. State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China. [email protected].
  • # Contributed equally.
PMID: 42342646 DOI: 10.1038/s41421-026-00898-1
Abstract

The recruitment and condensation of apoptosis-associated speck-like protein containing a CARD (ASC) are critical for ASC speck formation and inflammasome activation. However, how this process occurs efficiently in vivo remains unclear. Here, we identified the RNA helicase DDX6 as an ASC-interacting protein through immunoprecipitation‒mass spectrometry (IP‒MS) analysis. DDX6 promotes the activation of both NLRP3 and AIM2 inflammasomes by facilitating the recruitment of ASC to these receptors through its RNA helicase activity. Mechanistically, DDX6 functions as a scaffold protein for processing body (P-body) assembly and drives ASC speck formation in P-bodies via liquid‒liquid phase separation (LLPS). We report that membrane integrity is associated with stress granule (SG) formation and that in Caspase-1-/-, Gsdmd-/-, or NINJ1-inhibited cells, DDX6 mediates initial ASC speck assembly in P-bodies, followed by their transition to SGs during inflammasome activation. DDX6 deficiency in macrophages increases host susceptibility to Listeria Infection. Our results establish that DDX6 orchestrates ASC recruitment, speck formation, and subsequent transition through LLPS-mediated mechanisms, offering new insights into inflammasome assembly and potential therapeutic approaches for inflammasome-related diseases.

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