ABSTRACT
Inflammasomes are pivotal cytosolic molecular platforms involved in infection resistance. As multiprotein complexes, they consist of NOD-like receptors (NLRs), the adaptor proteins apoptosis-associated speck-like protein containing a CARD (ASC) and the effector molecules caspase-1 and caspase-11, whose assembly and activation depends on homotypic interactions. Here we describe WD repeat containing protein 90 (WDR90) as a new inflammasome component. We found that zebrafish wdr90 is highly induced by guanylate binding protein 4 (Gbp4) independently of inflammasome activation and caspase-1 activity. This gene encodes an evolutionarily conserved protein with unknown functions that contains several WD40 domains, which are involved in coordinating multiprotein complex assembly. Functional studies in zebrafish larvae showed that forced expression of wdr90 increased caspase-1 activity and inflammasome-dependent resistance to Salmonella enterica serovar Typhimurium infection. Wdr90 acted upstream of zebrafish caspase a (Caspa), the functional homolog of mammalian caspase-1, and Asc. Reconstitution experiments of the human inflammasome in HEK293â¯cells demonstrated that WDR90 was able to physically interact with and to alter the cellular distribution of NLRC4, but not of NLRP3 and AIM2. These results highlight the complexity of the inflammasome and the interest of studying fish immunity to understand not only the evolution of the immune system but also human immunity.
Subject(s)
CARD Signaling Adaptor Proteins/metabolism , Calcium-Binding Proteins/metabolism , Cytoskeletal Proteins/immunology , Inflammasomes/immunology , Salmonella Infections/immunology , Salmonella typhimurium/immunology , Zebrafish Proteins/immunology , Animals , CARD Signaling Adaptor Proteins/immunology , Calcium-Binding Proteins/immunology , Caspase 1/immunology , Caspase 1/metabolism , Cytoskeletal Proteins/metabolism , DNA-Binding Proteins/immunology , DNA-Binding Proteins/metabolism , Disease Models, Animal , Disease Resistance/immunology , GTP-Binding Proteins/metabolism , HEK293 Cells , Humans , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Protein Binding/immunology , Salmonella Infections/microbiology , Zebrafish , Zebrafish Proteins/metabolismABSTRACT
The zebrafish has unique advantages for understanding the evolution of vertebrate immunity and to model human diseases. In this review, we will firstly give an overview of the current knowledge on vertebrate innate immune receptors with special emphasis on the inflammasome and then summarize the main contribution of the zebrafish model to this field, including to the identification of novel inflammasome components and to the mechanisms involved in its activation, assembly and clearance of intracellular bacteria.
