Abstract
NF-kappaB (nuclear factor kappaB) has a pivotal role in many cellular processes, including the inflammatory and immune responses and, therefore, its activation is tightly regulated by the IKK (IkappaB kinase) complex and by IkappaBalpha degradation. When Shigella bacteria multiply within epithelial cells they release peptidoglycans, which are recognized by Nod1 and stimulate the NF-kappaB pathway, thus leading to a severe inflammatory response. Here, we show that IpaH9.8, a Shigella effector possessing E3 ligase activity, dampens the NF-kappaB-mediated inflammatory response to the bacterial infection in a unique way. IpaH9.8 interacts with NEMO/IKKgamma and ABIN-1, a ubiquitin-binding adaptor protein, promoting ABIN-1-dependent polyubiquitylation of NEMO. Consequently, polyubiquitylated NEMO undergoes proteasome-dependent degradation, which perturbs NF-kappaB activation. As NEMO is essential for NF-kappaB activation, we propose that the polyubiquitylation and degradation of NEMO during Shigella infection is a new bacterial strategy to modulate host inflammatory responses.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Bacterial / genetics
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Antigens, Bacterial / metabolism*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism*
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Cell Nucleus / metabolism
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Female
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Gene Expression Regulation
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HeLa Cells
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Humans
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism*
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Immunoprecipitation
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Inflammation / genetics
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Inflammation / metabolism*
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Inflammation / pathology
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Luciferases / metabolism
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Mice
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Mice, Inbred C57BL
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Pneumonia / genetics
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Pneumonia / metabolism
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Pneumonia / pathology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Recombinant Proteins / genetics
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Two-Hybrid System Techniques
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Ubiquitin / metabolism
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Ubiquitination
Substances
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Antigens, Bacterial
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Bacterial Proteins
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DNA-Binding Proteins
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IKBKG protein, human
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NF-kappa B
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RNA, Messenger
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RNA, Small Interfering
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Recombinant Proteins
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TNIP1 protein, human
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Ubiquitin
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ipaH protein, Shigella flexneri
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Luciferases
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I-kappa B Kinase