PUBLICATION

The zebrafish NLRP3 inflammasome has functional roles in ASC-dependent interleukin-1β maturation and gasdermin E-mediated pyroptosis

Authors
Li, J.Y., Wang, Y.Y., Shao, T., Fan, D.D., Lin, A.F., Xiang, L.X., Shao, J.Z.
ID
ZDB-PUB-191220-5
Date
2019
Source
The Journal of biological chemistry   295(4): 1120-1141 (Journal)
Registered Authors
Fan, Dongdong, Li, Jiangyuan, Lin, Aifu, Shao, Jian-zhong, Shao, Tong, Wang, Yueyi, Xiang, Lixin
Keywords
NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), caspase, gasdermin E (GSDME), inflammasome, innate immunity, interleukin 1 (IL-1), pattern recognition receptor, pyroptosis, zebrafish
MeSH Terms
  • Animals
  • Caspases/metabolism
  • Cytoskeletal Proteins/metabolism*
  • HEK293 Cells
  • Humans
  • Inflammasomes/metabolism*
  • Interleukin-1beta/metabolism*
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein/metabolism*
  • Protein Aggregates
  • Pyroptosis*
  • Receptors, Estrogen/chemistry
  • Receptors, Estrogen/metabolism*
  • Zebrafish/metabolism*
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/metabolism*
PubMed
31852739 Full text @ J. Biol. Chem.
Abstract
The NLR family pyrin domain containing 3 (NLRP3) inflammasome is one of the best characterized inflammasomes in humans and other mammals. However, knowledge about the NLRP3 inflammasome in non-mammalian species remains limited. Here, we report the molecular and functional identification of an NLRP3 homolog (DrNLRP3) in a zebrafish (Danio rerio) model. We found that DrNLRP3's overall structural architecture shared with mammalian NLRP3s. It initiates a classical inflammasome assembly for zebrafish inflammatory caspases (DrCaspase-A/-B) activation and interleukin 1β (DrIL-1β) maturation in an apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent manner, in which DrNLRP3 organizes DrASC into a filament that recruits DrCaspase-A/-B by homotypic pyrin domain (PYD)-PYD interactions. DrCaspase-A/-B activation in the DrNLRP3 inflammasome occurred in two steps, with DrCaspase-A being activated first and DrCaspase-B second. DrNLRP3 also directly activated full-length DrCaspase-B and elicited cell pyroptosis in a gasdermin E (GSDME)-dependent but ASC-independent manner. These two events were tightly coordinated by DrNLRP3 to ensure efficient IL-1β secretion for the initiation of host innate immunity. By knocking down DrNLRP3 in zebrafish embryos and generating a DrASC-knockout (DrASC-/-) fish clone, we characterized the function of the DrNLRP3 inflammasome in anti-bacterial immunity in vivo The results of our study disclosed the origin of the NLRP3 inflammasome in teleost fish, providing a cross-species understanding of the evolutionary history of inflammasomes. Our findings also indicate that the NLRP3 inflammasome may coordinate inflammatory cytokine processing and secretion through a GSDME-mediated pyroptotic pathway, uncovering a previously unrecognized regulatory function of NLRP3 in both inflammation and cell pyroptosis.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
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Mapping