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

Dong Min Shin, Bo Young Jeon, Hye Mi Lee, Hyo Sun Jin, Jae Min Yuk, Chang Hwa Song, Sang Hee Lee, Zee Won Lee, Sangnae Cho, Jin Man Kim, Richard L. Friedman, Eun Kyeong Jo

Research output: Contribution to journalArticle

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Abstract

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-Deis) displayed markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo. Infection of macrophages with Mtb-Deis increased the production of tumor necrosis factor-a and interleukin-6 over the levels produced by infection with wild-type or complemented strains. Elevated ROS generation in macrophages infected with Mtb-Deis (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-Deis 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.

Original languageEnglish
Article numbere1001230
JournalPLoS Pathogens
Volume6
Issue number12
DOIs
Publication statusPublished - 2010 Dec 1

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Autophagy
Mycobacterium tuberculosis
Oxidation-Reduction
Cell Death
Inflammation
Macrophages
Reactive Oxygen Species
Smegma
Cytokines
Acetyltransferases
JNK Mitogen-Activated Protein Kinases
NADPH Oxidase
Caspases
Vacuoles
Infection
Interleukin-6
Cell Survival
Mitochondria
Oxidative Stress
Tumor Necrosis Factor-alpha

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Shin, D. M., Jeon, B. Y., Lee, H. M., Jin, H. S., Yuk, J. M., Song, C. H., ... Jo, E. K. (2010). Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling. PLoS Pathogens, 6(12), [e1001230]. https://doi.org/10.1371/journal.ppat.1001230
Shin, Dong Min ; Jeon, Bo Young ; Lee, Hye Mi ; Jin, Hyo Sun ; Yuk, Jae Min ; Song, Chang Hwa ; Lee, Sang Hee ; Lee, Zee Won ; Cho, Sangnae ; Kim, Jin Man ; Friedman, Richard L. ; Jo, Eun Kyeong. / Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling. In: PLoS Pathogens. 2010 ; Vol. 6, No. 12.
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Shin, DM, Jeon, BY, Lee, HM, Jin, HS, Yuk, JM, Song, CH, Lee, SH, Lee, ZW, Cho, S, Kim, JM, Friedman, RL & Jo, EK 2010, 'Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling', PLoS Pathogens, vol. 6, no. 12, e1001230. https://doi.org/10.1371/journal.ppat.1001230

Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling. / Shin, Dong Min; Jeon, Bo Young; Lee, Hye Mi; Jin, Hyo Sun; Yuk, Jae Min; Song, Chang Hwa; Lee, Sang Hee; Lee, Zee Won; Cho, Sangnae; Kim, Jin Man; Friedman, Richard L.; Jo, Eun Kyeong.

In: PLoS Pathogens, Vol. 6, No. 12, e1001230, 01.12.2010.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling

AU - Shin, Dong Min

AU - Jeon, Bo Young

AU - Lee, Hye Mi

AU - Jin, Hyo Sun

AU - Yuk, Jae Min

AU - Song, Chang Hwa

AU - Lee, Sang Hee

AU - Lee, Zee Won

AU - Cho, Sangnae

AU - Kim, Jin Man

AU - Friedman, Richard L.

AU - Jo, Eun Kyeong

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N2 - 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-Deis) displayed markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo. Infection of macrophages with Mtb-Deis increased the production of tumor necrosis factor-a and interleukin-6 over the levels produced by infection with wild-type or complemented strains. Elevated ROS generation in macrophages infected with Mtb-Deis (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-Deis 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.

AB - 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-Deis) displayed markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo. Infection of macrophages with Mtb-Deis increased the production of tumor necrosis factor-a and interleukin-6 over the levels produced by infection with wild-type or complemented strains. Elevated ROS generation in macrophages infected with Mtb-Deis (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-Deis 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.

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