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ChNLRC4, a cytoplasmic pattern recognition receptor, activates the pyroptosis signaling pathway in Mollusca

Tianxiang Lin1, Lu Liu1, Liang Zeng1

  • 1Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, 100049, China.

International Journal of Biological Macromolecules
|January 10, 2025
PubMed

Insights

This study identifies ChNLRC4, an oyster protein that activates ChCaspase-1 and ChGSDME, initiating pyroptosis. This discovery reveals a novel NLR-Caspase-GSDME pathway crucial for oyster immunity and bacterial clearance.

Area of Science:

  • Immunology
  • Molecular Biology
  • Marine Biology

Background:

  • NLR inflammasomes trigger pyroptosis via Caspase-1 and GSDMD in mammals.
  • The NLR-Caspase-GSDME axis in invertebrates remains largely uncharacterized.

Purpose of the Study:

  • To investigate the existence and function of an NLR-Caspase-GSDME pathway in oysters.
  • To characterize the role of oyster NLRC4 (ChNLRC4) in immune signaling.

Main Methods:

  • Identified and characterized ChNLRC4, an oyster NLRC4 homolog.
  • Investigated ChNLRC4's binding to LPS and PGN via its LRR domain.
  • Examined ChNLRC4 interactions with ChCaspase-1 using CARD-CARD domain interactions.
  • Assessed ChNLRC4's role in ChGSDME cleavage and pyroptosis induction in HEK293T cells.
  • Analyzed the effects of ChNLRC4 knockdown on oyster hemocyte immune responses and bacterial clearance.

Main Results:

  • ChNLRC4 binds to LPS and Lys-type PGN.
  • ChNLRC4 interacts with ChCaspase-1, enhancing its activity.
  • Overexpression of ChNLRC4 promotes ChCaspase-1-mediated ChGSDME cleavage and pyroptosis.
  • ChNLRC4 knockdown significantly reduces hemocyte death, immune infiltration, and improves bacterial clearance.

Conclusions:

  • This study elucidates a novel NLR-Caspase-GSDME pyroptosis pathway in oysters.
  • ChNLRC4 plays a critical role in oyster innate immunity against bacterial infections.
  • The findings provide insights into the evolution and function of NLR inflammasomes in invertebrates.
Keywords:
ChCaspase-1ChGSDMEChNLRC4Crassostrea hongkongensisPyroptosis

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