Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling.

The "enhanced intracellular survival" (eis) gene of Mycobacterium tuberculosis (Mtb) is involved in the intracellular survival of M. smegmatis. However, its exact effects on host cell function remain elusive. We herein report that Mtb Eis plays essential roles in modulating macrophage auto...

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Autores principales:	Dong-Min Shin, Bo-Young Jeon, Hye-Mi Lee, Hyo Sun Jin, Jae-Min Yuk, Chang-Hwa Song, Sang-Hee Lee, Zee-Won Lee, Sang-Nae Cho, Jin-Man Kim, Richard L Friedman, Eun-Kyeong Jo
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/7a68f703324c4101bda1cdde14254c6b
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spelling	oai:doaj.org-article:7a68f703324c4101bda1cdde14254c6b2021-11-18T06:03:44ZMycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling.1553-73661553-737410.1371/journal.ppat.1001230https://doaj.org/article/7a68f703324c4101bda1cdde14254c6b2010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21187903/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The "enhanced intracellular survival" (eis) gene of Mycobacterium tuberculosis (Mtb) is involved in the intracellular survival of M. smegmatis. However, its exact effects on host cell function remain elusive. We herein report that Mtb Eis plays essential roles in modulating macrophage autophagy, inflammatory responses, and cell death via a reactive oxygen species (ROS)-dependent pathway. Macrophages infected with an Mtb eis-deletion mutant H37Rv (Mtb-Δeis) displayed markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo. Infection of macrophages with Mtb-Δeis increased the production of tumor necrosis factor-α and interleukin-6 over the levels produced by infection with wild-type or complemented strains. Elevated ROS generation in macrophages infected with Mtb-Δeis (for which NADPH oxidase and mitochondria were largely responsible) rendered the cells highly sensitive to autophagy activation and cytokine production. Despite considerable activation of autophagy and proinflammatory responses, macrophages infected with Mtb-Δeis underwent caspase-independent cell death. This cell death was significantly inhibited by blockade of autophagy and c-Jun N-terminal kinase-ROS signaling, suggesting that excessive autophagy and oxidative stress are detrimental to cell survival. Finally, artificial over-expression of Eis or pretreatment with recombinant Eis abrogated production of both ROS and proinflammatory cytokines, which depends on the N-acetyltransferase domain of the Eis protein. Collectively, these data indicate that Mtb Eis suppresses host innate immune defenses by modulating autophagy, inflammation, and cell death in a redox-dependent manner.Dong-Min ShinBo-Young JeonHye-Mi LeeHyo Sun JinJae-Min YukChang-Hwa SongSang-Hee LeeZee-Won LeeSang-Nae ChoJin-Man KimRichard L FriedmanEun-Kyeong JoPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 12, p e1001230 (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 Dong-Min Shin Bo-Young Jeon Hye-Mi Lee Hyo Sun Jin Jae-Min Yuk Chang-Hwa Song Sang-Hee Lee Zee-Won Lee Sang-Nae Cho Jin-Man Kim Richard L Friedman Eun-Kyeong Jo Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling.
description	The "enhanced intracellular survival" (eis) gene of Mycobacterium tuberculosis (Mtb) is involved in the intracellular survival of M. smegmatis. However, its exact effects on host cell function remain elusive. We herein report that Mtb Eis plays essential roles in modulating macrophage autophagy, inflammatory responses, and cell death via a reactive oxygen species (ROS)-dependent pathway. Macrophages infected with an Mtb eis-deletion mutant H37Rv (Mtb-Δeis) displayed markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo. Infection of macrophages with Mtb-Δeis increased the production of tumor necrosis factor-α and interleukin-6 over the levels produced by infection with wild-type or complemented strains. Elevated ROS generation in macrophages infected with Mtb-Δeis (for which NADPH oxidase and mitochondria were largely responsible) rendered the cells highly sensitive to autophagy activation and cytokine production. Despite considerable activation of autophagy and proinflammatory responses, macrophages infected with Mtb-Δeis underwent caspase-independent cell death. This cell death was significantly inhibited by blockade of autophagy and c-Jun N-terminal kinase-ROS signaling, suggesting that excessive autophagy and oxidative stress are detrimental to cell survival. Finally, artificial over-expression of Eis or pretreatment with recombinant Eis abrogated production of both ROS and proinflammatory cytokines, which depends on the N-acetyltransferase domain of the Eis protein. Collectively, these data indicate that Mtb Eis suppresses host innate immune defenses by modulating autophagy, inflammation, and cell death in a redox-dependent manner.
format	article
author	Dong-Min Shin Bo-Young Jeon Hye-Mi Lee Hyo Sun Jin Jae-Min Yuk Chang-Hwa Song Sang-Hee Lee Zee-Won Lee Sang-Nae Cho Jin-Man Kim Richard L Friedman Eun-Kyeong Jo
author_facet	Dong-Min Shin Bo-Young Jeon Hye-Mi Lee Hyo Sun Jin Jae-Min Yuk Chang-Hwa Song Sang-Hee Lee Zee-Won Lee Sang-Nae Cho Jin-Man Kim Richard L Friedman Eun-Kyeong Jo
author_sort	Dong-Min Shin
title	Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling.
title_short	Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling.
title_full	Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling.
title_fullStr	Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling.
title_full_unstemmed	Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling.
title_sort	mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/7a68f703324c4101bda1cdde14254c6b
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Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling.

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