The Bacterial T6SS Effector EvpP Prevents NLRP3 Inflammasome Activation by Inhibiting the Ca 2+ -Dependent MAPK-Jnk Pathway

Inflammasome activation is an important innate immune defense mechanism against bacterial infection, and in return, bacteria express virulence determinants that counteract inflammasome activation. Many such effectors are secreted into host cells via specialized bacterial secretion systems. Here, the...

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Published in:Cell host & microbe 2017-01, Vol.21 (1), p.47
Main Authors: Chen, Hao, Yang, Dahai, Han, Fajun, Tan, Jinchao, Zhang, Lingzhi, Xiao, Jingfan, Zhang, Yuanxing, Liu, Qin
Format: Article
Language:English
Subjects:
Animals
Apoptosis Regulatory Proteins - metabolism
Calcium-Binding Proteins - metabolism
Cell Line, Tumor
Edwardsiella tarda - immunology
Edwardsiella tarda - metabolism
Enzyme Activation
HEK293 Cells
HeLa Cells
Humans
Inflammasomes - metabolism
JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors
L Cells (Cell Line)
MAP Kinase Signaling System - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
Type III Secretion Systems - metabolism
Type VI Secretion Systems - metabolism
Virulence Factors - metabolism
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Summary:Inflammasome activation is an important innate immune defense mechanism against bacterial infection, and in return, bacteria express virulence determinants that counteract inflammasome activation. Many such effectors are secreted into host cells via specialized bacterial secretion systems. Here, the intracellular pathogenic bacterium Edwardsiella tarda was demonstrated to activate NLRC4 and NLRP3 inflammasomes via a type III secretion system (T3SS), and to inhibit NLRP3 inflammasome via a type VI secretion system (T6SS), indicating the antagonistic roles of these systems in inflammasome signaling. Furthermore, a non-VgrG T6SS effector, EvpP, was identified that significantly inhibited NLRP3 inflammasome activation. Subsequent studies revealed that EvpP significantly suppressed Jnk activation, thus impairing oligomerization of the inflammasome adaptor ASC. Moreover, EvpP counteracted cytoplasmic Ca increase, which works upstream of Jnk activation to regulate the NLRP3 inflammasome. Finally, EvpP-mediated inflammasome inhibition promoted bacterial colonization in vivo. This work expands our understanding of bacterial T6SS in counteracting host immune responses.
ISSN:1934-6069