NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.

The NF-κB signaling pathway is central to the innate and adaptive immune responses. Upon their detection of pathogen-associated molecular patterns, Toll-like receptors on the cell surface initiate signal transduction and activate the NF-κB pathway, leading to the production of a wide array of inflam...

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Autores principales:	Hilo Yen, Tadasuke Ooka, Atsushi Iguchi, Tetsuya Hayashi, Nakaba Sugimoto, Toru Tobe
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/49f1ab90b9bf41cbb10da9c2ed90affa
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spelling	oai:doaj.org-article:49f1ab90b9bf41cbb10da9c2ed90affa2021-11-18T06:03:44ZNleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.1553-73661553-737410.1371/journal.ppat.1001231https://doaj.org/article/49f1ab90b9bf41cbb10da9c2ed90affa2010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21187904/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The NF-κB signaling pathway is central to the innate and adaptive immune responses. Upon their detection of pathogen-associated molecular patterns, Toll-like receptors on the cell surface initiate signal transduction and activate the NF-κB pathway, leading to the production of a wide array of inflammatory cytokines, in attempt to eradicate the invaders. As a countermeasure, pathogens have evolved ways to subvert and manipulate this system to their advantage. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) are closely related bacteria responsible for major food-borne diseases worldwide. Via a needle-like protein complex called the type three secretion system (T3SS), these pathogens deliver virulence factors directly to host cells and modify cellular functions, including by suppressing the inflammatory response. Using gain- and loss-of-function screenings, we identified two bacterial effectors, NleC and NleE, that down-regulate the NF-κB signal upon being injected into a host cell via the T3SS. A recent report showed that NleE inhibits NF-κB activation, although an NleE-deficient pathogen was still immune-suppressive, indicating that other anti-inflammatory effectors are involved. In agreement, our present results showed that NleC was also required to inhibit inflammation. We found that NleC is a zinc protease that disrupts NF-κB activation by the direct cleavage of NF-κB's p65 subunit in the cytoplasm, thereby decreasing the available p65 and reducing the total nuclear entry of active p65. More importantly, we showed that a mutant EPEC/EHEC lacking both NleC and NleE (ΔnleC ΔnleE) caused greater inflammatory response than bacteria carrying ΔnleC or ΔnleE alone. This effect was similar to that of a T3SS-defective mutant. In conclusion, we found that NleC is an anti-inflammatory bacterial zinc protease, and that the cooperative function of NleE and NleC disrupts the NF-κB pathway and accounts for most of the immune suppression caused by EHEC/EPEC.Hilo YenTadasuke OokaAtsushi IguchiTetsuya HayashiNakaba SugimotoToru TobePublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 12, p e1001231 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Hilo Yen Tadasuke Ooka Atsushi Iguchi Tetsuya Hayashi Nakaba Sugimoto Toru Tobe NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.
description	The NF-κB signaling pathway is central to the innate and adaptive immune responses. Upon their detection of pathogen-associated molecular patterns, Toll-like receptors on the cell surface initiate signal transduction and activate the NF-κB pathway, leading to the production of a wide array of inflammatory cytokines, in attempt to eradicate the invaders. As a countermeasure, pathogens have evolved ways to subvert and manipulate this system to their advantage. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) are closely related bacteria responsible for major food-borne diseases worldwide. Via a needle-like protein complex called the type three secretion system (T3SS), these pathogens deliver virulence factors directly to host cells and modify cellular functions, including by suppressing the inflammatory response. Using gain- and loss-of-function screenings, we identified two bacterial effectors, NleC and NleE, that down-regulate the NF-κB signal upon being injected into a host cell via the T3SS. A recent report showed that NleE inhibits NF-κB activation, although an NleE-deficient pathogen was still immune-suppressive, indicating that other anti-inflammatory effectors are involved. In agreement, our present results showed that NleC was also required to inhibit inflammation. We found that NleC is a zinc protease that disrupts NF-κB activation by the direct cleavage of NF-κB's p65 subunit in the cytoplasm, thereby decreasing the available p65 and reducing the total nuclear entry of active p65. More importantly, we showed that a mutant EPEC/EHEC lacking both NleC and NleE (ΔnleC ΔnleE) caused greater inflammatory response than bacteria carrying ΔnleC or ΔnleE alone. This effect was similar to that of a T3SS-defective mutant. In conclusion, we found that NleC is an anti-inflammatory bacterial zinc protease, and that the cooperative function of NleE and NleC disrupts the NF-κB pathway and accounts for most of the immune suppression caused by EHEC/EPEC.
format	article
author	Hilo Yen Tadasuke Ooka Atsushi Iguchi Tetsuya Hayashi Nakaba Sugimoto Toru Tobe
author_facet	Hilo Yen Tadasuke Ooka Atsushi Iguchi Tetsuya Hayashi Nakaba Sugimoto Toru Tobe
author_sort	Hilo Yen
title	NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.
title_short	NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.
title_full	NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.
title_fullStr	NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.
title_full_unstemmed	NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.
title_sort	nlec, a type iii secretion protease, compromises nf-κb activation by targeting p65/rela.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/49f1ab90b9bf41cbb10da9c2ed90affa
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NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA.

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