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

Tianxiang Lin; Lu Liu; Liang Zeng; Congxin Zhao; Shu Xiao; Haitao Ma; Jun Li; Fan Mao; Yanping Qin; Yuehuan Zhang; Yang Zhang; Zhiming Xiang; Ziniu Yu

doi:10.1016/j.ijbiomac.2025.139632

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

Int J Biol Macromol. 2025 Jan 8:139632. doi: 10.1016/j.ijbiomac.2025.139632. Online ahead of print.

Authors

Tianxiang Lin¹, Lu Liu¹, Liang Zeng¹, Congxin Zhao¹, Shu Xiao¹, Haitao Ma¹, Jun Li¹, Fan Mao¹, Yanping Qin¹, Yuehuan Zhang¹, Yang Zhang¹, Zhiming Xiang², Ziniu Yu¹

Affiliations

¹ Key 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.
² Key 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. Electronic address: zhimingxiang@scsio.ac.cn.

PMID: 39793815
DOI: 10.1016/j.ijbiomac.2025.139632

Abstract

NLR inflammasomes recognize pathogen-associated molecular patterns (PAMPs), triggering Caspase-1 activation and leading to gasdermin D (GSDMD)-mediated pyroptosis, a crucial immune response in mammals. The functional GSDME-mediated pyroptosis has been reported in invertebrates, yet the existence of an NLR-Caspase-GSDME axis mediating pyroptosis signaling cascades remains unclear. In this study, we reported an NLRC4 homolog named ChNLRC4, a pattern recognition receptor from the oyster Crassostrea hongkongensis that is able to bind to LPS and Lys-type PGN through its LRR domain. ChNLRC4 interacted with ChCaspase-1 through CARD-CARD domain homotypic interactions and enhanced ChCaspase-1 activity. Additionally, overexpression of ChNLRC4 promoted ChCaspase-1-mediated cleavage of ChGSDME, leading to pyroptosis in HEK293T cells. Furthermore, knockdown of chnlrc4 resulted in a significant reduction in the death rate of hemocytes, immune infiltration of hemocytes, cilium shedding, and bacterial clearance. Collectively, this study provides insight into the role of NLR within the pyroptosis signaling pathway in oysters.

Keywords: ChCaspase-1; ChGSDME; ChNLRC4; Crassostrea hongkongensis; Pyroptosis.