Sensing of cytosolic LPS through caspy2 pyrin domain mediates noncanonical inflammasome activation in zebrafish

• Published in: Nature communications Vol. 9; no. 1; pp. 3052 - 12
• Main Authors: Yang, Dahai, Zheng, Xin, Chen, Shouwen, Wang, Zhuang, Xu, Wenting, Tan, Jinchao, Hu, Tianjian, Hou, Mingyu, Wang, Wenhui, Gu, Zhaoyan, Wang, Qiyao, Zhang, Ruilin, Zhang, Yuanxing, Liu, Qin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/63; 631/181/2806; 631/181/735; 631/250/2499; 631/250/256/1980; 631/250/256/2177; 82/1; 82/80; Activation; Animals; Bacterial diseases; Bacterial infections; Bacterial Infections - immunology; Caspase; Caspase-5; Caspases - drug effects; Caspases - genetics; Caspases - immunology; Caspases - metabolism; CRISPR-Cas Systems; Cytosol - metabolism; Danio rerio; Detection; Disease Models, Animal; Fibroblasts; Fibroblasts - immunology; Gastrointestinal Tract - pathology; Gene Knockdown Techniques; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Immunity; Immunity, Innate; Inflammasomes; Inflammasomes - metabolism; Inflammation; Innate immunity; Larvae; Lipopolysaccharides; Lipopolysaccharides - toxicity; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein; Oligomerization; Pattern recognition; Pyrin Domain - physiology; Pyrin protein; Pyroptosis; Pyroptosis - immunology; Science; Science (multidisciplinary); Sepsis; Sepsis - microbiology; Zebrafish; Zebrafish - immunology; Zebrafish - microbiology; Zebrafish Proteins - drug effects; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04984-1

The noncanonical inflammasome is critical for cytosolic sensing of Gram-negative pathogens. Here, we show that bacterial infection induces caspy2 activation in zebrafish fibroblasts, which mediates pyroptosis via a caspase-5-like activity. Zebrafish caspy2 binds directly to lipopolysaccharide via the N-terminal pyrin death domain, resulting in caspy2 oligomerization, which is critical for pyroptosis. Furthermore, we show that caspy2 is highly expressed in the zebrafish gut and is activated during infection. Knockdown of caspy2 expression impairs the ability of zebrafish to restrict bacterial invasion in vivo, and protects larvae from lethal sepsis. Collectively, our results identify a crucial event in the evolution of pattern recognition into the death domain superfamily-mediated intracellular lipopolysaccharide-sensing pathway in innate immunity. In humans, caspase-5 is an LPS sensor that can induce gasdermin D cleavage and pyroptosis. Here, the authors show that zebrafish caspy2 is a functional homolog as it also senses cytosolic LPS to activate the noncanonical inflammasome and to protect against bacterial infection, but it does so via pyrin death domain interactions.