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      Shigella IpaH0722 E3 Ubiquitin Ligase Effector Targets TRAF2 to Inhibit PKC–NF-κB Activity in Invaded Epithelial Cells

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          Abstract

          NF-κB plays a central role in modulating innate immune responses to bacterial infections. Therefore, many bacterial pathogens deploy multiple mechanisms to counteract NF-κB activation. The invasion of and subsequent replication of Shigella within epithelial cells is recognized by various pathogen recognition receptors as pathogen-associated molecular patterns. These receptors trigger innate defense mechanisms via the activation of the NF-κB signaling pathway. Here, we show the inhibition of the NF-κB activation by the delivery of the IpaH E3 ubiquitin ligase family member IpaH0722 using Shigella's type III secretion system. IpaH0722 dampens the acute inflammatory response by preferentially inhibiting the PKC-mediated activation of NF-κB by ubiquitinating TRAF2, a molecule downstream of PKC, and by promoting its proteasome-dependent degradation.

          Author Summary

          In response to bacterial infection, host cells induce a plethora of innate immune responses to combat the infection. However, many bacterial pathogens have developed sophisticated mechanisms to evade the host's immune system. Because NF-κB is crucial for innate immune responses against bacterial infection, bacterial pathogens deploy multiple countermeasures to inhibit NF-κB activation. The invasion and replication of Shigella within host cells results in cellular damage and the production of bacterial components that trigger NF-κB activation. Here, we show that the Shigella type III secretion system (T3SS) effector IpaH0722, a member of the IpaH E3 ubiquitin ligase family, inhibits NF-κB activation during Shigella infection. IpaH0722 preferentially targets the PKC–NF-κB pathway, which is activated in response to danger signals caused by disruption of the phagosomal membrane during the dissemination of Shigella into the cytoplasm. IpaH0722 inhibits NF-κB activation by targeting TRAF2, which lies downstream of PKC, for ubiquitination and proteasome-dependent degradation.

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          Most cited references47

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          Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan.

          Although the role of Toll-like receptors in extracellular bacterial sensing has been investigated intensively, intracellular detection of bacteria through Nod molecules remains largely uncharacterized. Here, we show that human Nod1 specifically detects a unique diaminopimelate-containing N-acetylglucosamine-N-acetylmuramic acid (GlcNAc-MurNAc) tripeptide motif found in Gram-negative bacterial peptidoglycan, resulting in activation of the transcription factor NF-kappaB pathway. Moreover, we show that in epithelial cells (which represent the first line of defense against invasive pathogens), Nod1is indispensable for intracellular Gram-negative bacterial sensing.
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            Bacterial invasion: the paradigms of enteroinvasive pathogens.

            Invasive bacteria actively induce their own uptake by phagocytosis in normally nonphagocytic cells and then either establish a protected niche within which they survive and replicate, or disseminate from cell to cell by means of an actin-based motility process. The mechanisms underlying bacterial entry, phagosome maturation, and dissemination reveal common strategies as well as unique tactics evolved by individual species to establish infection.
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              Ubiquitylation in innate and adaptive immunity.

              Protein ubiquitylation has emerged as a key mechanism that regulates immune responses. Much like phosphorylation, ubiquitylation is a reversible covalent modification that regulates the stability, activity and localization of target proteins. As such, ubiquitylation regulates the development of the immune system and many phases of the immune response, including its initiation, propagation and termination. Recent work has shown that several ubiquitin ligases help to prevent the immune system from attacking self tissues. The dysfunction of several ubiquitin ligases has been linked to autoimmune diseases.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                June 2013
                June 2013
                6 June 2013
                : 9
                : 6
                : e1003409
                Affiliations
                [1 ]Division of Bacterial Infection Biology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan
                [2 ]Department of Immunology, Juntendo University School Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan
                [3 ]Nippon Institute for Biological Science, Shinmachi, Ome, Tokyo, Japan
                [4 ]Medical Mycology Research Center, Chiba University, Inohana, Chuo-ku, Chiba, Japan
                Collège de France, France
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: HA. Performed the experiments: HA. Analyzed the data: HA CS. Contributed reagents/materials/analysis tools: HA HN. Wrote the paper: HA CS.

                Article
                PPATHOGENS-D-12-02266
                10.1371/journal.ppat.1003409
                3675035
                23754945
                756b455f-1c43-41bc-a560-dc2913fb600d
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 September 2012
                : 23 April 2013
                Page count
                Pages: 15
                Funding
                This work was supported by Grant-in-Aid for Specially Promoted Research (23000012 (CS)); a Grant-in-Aid for Young Scientists (B) (23790472 (HA)) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Part of this work was supported by grants from the Naito Foundation (HA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Microbiology
                Bacterial Pathogens
                Host-Pathogen Interaction

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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