Shigella hijacks the glomulin–cIAPs–inflammasome axis to promote inflammation |
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| Authors: | Shiho Suzuki Toshihiko Suzuki Hitomi Mimuro Tsunehiro Mizushima Chihiro Sasakawa |
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| Affiliation: | 1. Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan;2. Department of Bacterial Infection and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;3. Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan;4. Department of Infection Microbiology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;5. Picobiology Institute, Graduate School of Life Science, University of Hyogo, Hyogo, Japan;6. Medical Mycology Research Center, Chiba University, Chiba, Japan;7. Nippon Institute for Biological Science, Tokyo, Japan |
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| Abstract: | 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 (cIAP1 and cIAP2), 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 siRNA‐mediated knockdown, enhances inflammasome activation in response to infection by Shigella, Salmonella, or Pseudomonas, stimulation with NLRP3 inflammasome activators (including SiO2, alum, or MSU), or stimulation of the AIM2 inflammasome by poly dA:dT. GLMN binds specifically to the RING domain of both cIAPs, 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. |
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| Keywords: | cIAPs
GLMN
inflammasome activation
Shigella
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