The Bacterial T6SS Effector EvpP Prevents NLRP3 Inflammasome Activation by Inhibiting the Ca2+-Dependent MAPK-Jnk Pathway

• Published in: Cell host & microbe Vol. 21; no. 1; pp. 47 - 58
• Main Authors: Chen, Hao, Yang, Dahai, Han, Fajun, Tan, Jinchao, Zhang, Lingzhi, Xiao, Jingfan, Zhang, Yuanxing, Liu, Qin
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 11.01.2017
• Subjects: ASC oligomerization; calcium; Jnk; NLRP3 inflammasome; T6SS effector; calcium; T6SS effector; NLRP3 inflammasome; ASC oligomerization; Jnk
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2016.12.004

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 Ca2+ 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. [Display omitted] •E. tarda utilizes a T6SS to negatively regulate NLRP3 inflammasome activation•The T6SS effector EvpP is identified and shown to inhibit NLRP3 inflammasome•EvpP suppresses ASC oligomerization by regulating a Ca2+-dependent Jnk pathway•EvpP-mediated inflammasome inhibition promotes E. tarda colonization in mice Edwardsiella tarda is an important pathogenic bacterium infecting a wide range of hosts from fish to humans. Chen et al. identify a novel T6SS effector, EvpP, in E. tarda that targets intracellular Ca2+ signaling to impair Jnk activation and subsequent ASC oligomerization, which promotes bacterial colonization in mice.