Grass carp NLRP12-like 2 facilitates GCRV replication by disrupting the NLRP3-ASC inflammasome axis.

Abstract

The cytosolic NOD-like receptor NLRP12 is a critical modulator of inflammatory responses, yet its function in teleost fish remains largely unexplored. This study investigated the functional role of grass carp (Ctenopharyngodon idella) NLRP12-like 2 in regulating host antiviral immune responses during GCRV infection. We first demonstrated that NLRP12-like 2 was ubiquitously expressed in vivo, and its transcriptional response to GCRV infection exhibited distinct, tissue-specific patterns. Functional assays in vitro revealed that overexpression of NLRP12-like 2 in CIK cells significantly facilitated GCRV replication, as evidenced by increased viral titers, enhanced viral gene (NS38 and VP3) expression, and exacerbated virus-induced cytotoxicity. Mechanistically, NLRP12-like 2 was found to act as a potent negative regulator of the inflammasome pathway: it suppressed caspase-1 activity and downregulated the transcription of downstream inflammatory mediators (IL-1β, TNFα, and GSDMD). Furthermore, we identified that NLRP12-like 2 interacted with the adaptor protein ASC and competitively disrupted the formation of the NLRP3-ASC inflammasome complex, leading to the dampening of caspase-1 activation. Our findings unveil a novel strategy in which NLRP12-like 2 impairs the NLRP3-ASC interaction, leading to the suppressed caspase-1 activation and inhibition of downstream inflammatory signaling, which in turn establishes a permissive cellular environment for GCRV replication.