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조회 4488  인쇄하기 주소복사 트위터 공유 페이스북 공유 
Mycobacterium tuberculosis Eis Regulates Autophagy, Inflammation, and Cell Death through Redox-dependent Signaling

Dong-Min Shin1,2#, Bo-Young Jeon3#, Hye-Mi Lee1,2, Hyo Sun Jin1,2, Jae-Min Yuk1,2, Chang-Hwa Song1, Sang-Hee Lee2,4, Zee-Won Lee5, Sang-Nae Cho3, Jin-Man Kim2,4, Richard L. Friedman6, Eun-Kyeong Jo1,2*

1 Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, Korea, 2 Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, Korea, 3 Department of Microbiology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea, 4 Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Korea, 5 Division of Life Science, Korea Basic Science Institute, Daejeon, Korea, 6 Department of Immunobiology, University of Arizona, Tucson, Arizona, United States of America

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-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.

Citation: Shin D-M, Jeon B-Y, Lee H-M, Jin HS, Yuk J-M, et al. (2010) Mycobacterium tuberculosis Eis Regulates Autophagy, Inflammation, and Cell Death through Redox-dependent Signaling. PLoS Pathog 6(12): e1001230. doi:10.1371/journal.ppat.1001230

Editor: Vojo Deretic, University of New Mexico, United States of America

Received: April 7, 2010; Accepted: November 15, 2010; Published: December 16, 2010

Copyright: ⓒ 2010 Shin et al. 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.

Funding: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (R13-2007-020-01000-0). Those providing funding had no role in study design, data collection and analysis, the decision to publish, or manuscript preparation.

Competing interests: The authors have declared that no competing interests exist.

논문정보 F1000선정
- 형식: Research article
- 게재일: 2010년 12월 (BRIC 등록일 2011-09-29)
- 연구진: 국내(교신)+국외 연구진태극기
- 분야: Microbiology, Parasitology
- 추천: Faculty of 1000 Biology
- 추천사유: Faculty of 1000 Biology:evaluations for Shin DM et al PLoS Pathog. 2010; 6(12):e1001230
http://f1000.com/13296996

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