Premium
Shigella hijacks the glomulin– cIAP s–inflammasome axis to promote inflammation
Author(s) -
Suzuki Shiho,
Suzuki Toshihiko,
Mimuro Hitomi,
Mizushima Tsunehiro,
Sasakawa Chihiro
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643841
Subject(s) - library science , medical school , medicine , microbiology and biotechnology , political science , biology , medical education , computer science
Shigella deploys a unique mechanism to manipulate macrophage pyroptosis by delivering the IpaH7.8 E3 ubiquitin ligase via its type III secretion system. IpaH7.8 ubiquitinates glomulin ( GLMN ) and elicits its degradation, thereby inducing inflammasome activation and pyroptotic cell death of macrophages. Here, we show that GLMN specifically binds cellular inhibitor of apoptosis proteins 1 and 2 ( cIAP 1 and cIAP 2), members of the inhibitor of apoptosis ( IAP ) family of RING ‐E3 ligases, which results in reduced E3 ligase activity, and consequently inflammasome‐mediated death of macrophages. Importantly, reducing the levels of GLMN in macrophages via IpaH7.8, or si RNA ‐mediated knockdown, enhances inflammasome activation in response to infection by Shigella, Salmonella, or Pseudomonas, stimulation with NLRP 3 inflammasome activators (including SiO 2 , alum, or MSU ), or stimulation of the AIM 2 inflammasome by poly dA : dT . GLMN binds specifically to the RING domain of both cIAP s, which inhibits their self‐ubiquitination activity. These findings suggest that GLMN is a negative regulator of cIAP ‐mediated inflammasome activation, and highlight a unique Shigella stratagem to kill macrophages, promoting severe inflammation.