Characterization of an NLRP1 Inflammasome from Zebrafish Reveals a Unique Sequential Activation Mechanism Underlying Inflammatory Caspases in Ancient Vertebrates

Li, J.Y., Gao, K., Shao, T., Fan, D.D., Hu, C.B., Sun, C.C., Dong, W.R., Lin, A.F., Xiang, L.X., Shao, J.Z.
Journal of immunology (Baltimore, Md. : 1950)   201(7): 1946-1966 (Journal)
Registered Authors
MeSH Terms
  • Adaptor Proteins, Signal Transducing/genetics
  • Animals
  • Apoptosis Regulatory Proteins/genetics
  • Apoptosis Regulatory Proteins/metabolism*
  • Biological Evolution
  • CARD Signaling Adaptor Proteins
  • Caspases/metabolism
  • Cloning, Molecular
  • Cytoskeletal Proteins/metabolism
  • Disease Models, Animal
  • Fish Proteins/genetics
  • Fish Proteins/metabolism
  • Humans
  • Inflammasomes/metabolism*
  • Inflammation/immunology*
  • Interleukin-1beta/metabolism
  • Models, Immunological
  • Protein Aggregation, Pathological
  • Vertebrates
  • Zebrafish/immunology*
  • Zebrafish Proteins/metabolism
30150286 Full text @ J. Immunol.
NLRP1 inflammasome is one of the best-characterized inflammasomes in humans and other mammals. However, the existence of this inflammasome in nonmammalian species remains poorly understood. In this study, we report the molecular and functional identification of an NLRP1 homolog, Danio rerio NLRP1 (DrNLRP1) from a zebrafish (D. rerio) model. This DrNLRP1 possesses similar structural architecture to mammalian NLRP1s. It can trigger the formation of a classical inflammasome for the activation of zebrafish inflammatory caspases (D. rerio Caspase [DrCaspase]-A and DrCaspase-B) and maturation of D. rerio IL-1β in a D. rerio ASC (DrASC)-dependent manner. In this process, DrNLRP1 promotes the aggregation of DrASC into a filament with DrASCCARD core and DrASCPYD cluster. The assembly of DrNLRP1 inflammasome depends on the CARD-CARD homotypic interaction between DrNLRP1 and DrASCCARD core, and PYD-PYD interaction between DrCaspase-A/B and DrASCPYD cluster. The FIIND domain in DrNLRP1 is necessary for inflammasome assembly. To understand the mechanism of how the two DrCaspases are coordinated in DrNLRP1 inflammasome, we propose a two-step sequential activation model. In this model, the recruitment and activation of DrCaspase-A/B in the inflammasome is shown in an alternate manner, with a preference for DrCaspase-A followed by a subsequent selection for DrCaspase-B. By using morpholino oligonucleotide-based knockdown assays, the DrNLRP1 inflammasome was verified to play important functional roles in antibacterial innate immunity in vivo. These observations demonstrate that the NLRP1 inflammasome originated as early as in teleost fish. This finding not only gives insights into the evolutionary history of inflammasomes but also provides a favorable animal model for the study of NLRP1 inflammasome-mediated immunology and diseases.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes