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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2.

Authors: Zhu, Lingxiang; Barrett, Erika C; Xu, Yuxue; Liu, Zuguo; Manoharan, Aditya; Chen, Yin

Published In PLoS One, (2013)

Abstract: Cigarette smoke (CS) has been reported to induce autophagy in airway epithelial cells. The subsequent autophagic cell death has been proposed to play an important pathogenic role in chronic obstructive pulmonary disease (COPD); however, the underlying molecular mechanism is not entirely clear. Using CS extract (CSE) as a surrogate for CS, we found that it markedly increased the expressions of both LC3B-I and LC3B-II as well as autophagosomes in airway epithelial cells. This is in contrast to the common autophagy inducer (i.e., starvation) that increases LC3B-II but reduces LC3B-I. Further studies indicate that CSE regulated LC3B at transcriptional and post-translational levels. In addition, CSE, but not starvation, activated Nrf2-mediated adaptive response. Increase of cellular Nrf2 by either Nrf2 overexpression or the knockdown of Keap1 (an Nrf2 inhibitor) significantly repressed CSE-induced LC3B-I and II as well as autophagosomes. Supplement of NAC (a GSH precursor) or GSH recapitulated the effect of Nrf2, suggesting the increase of cellular GSH level is responsible for Nrf2 effect on LC3B and autophagosome. Interestingly, neither Nrf2 activation nor GSH supplement could restore the repressed activities of mTOR or its downstream effctor-S6K. Thus, the Nrf2-dependent autophagy-suppression was not due to the re-activation of mTOR-the master repressor of autophagy. To search for the downstream effector of Nrf2 on LC3B and autophagosome, we tested Nrf2-dependent genes (i.e., NQO1 and P62) that are also increased by CSE treatment. We found that P62, but not NQO1, could mimic the effect of Nrf2 activation by repressing LC3B expression. Thus, Nrf2->P62 appears to play an important role in the regulation of CSE-induced LC3B and autophagosome.

PubMed ID: 23585825 Exiting the NIEHS site

MeSH Terms: Adaptor Proteins, Signal Transducing/genetics*; Adaptor Proteins, Signal Transducing/metabolism; Autophagy; Bronchi/cytology; Bronchi/drug effects*; Bronchi/metabolism; Cell Line; Complex Mixtures/isolation & purification; Complex Mixtures/pharmacology*; Epithelial Cells/cytology; Epithelial Cells/drug effects*; Epithelial Cells/metabolism; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Kelch-Like ECH-Associated Protein 1; Microtubule-Associated Proteins/genetics; Microtubule-Associated Proteins/metabolism; NF-E2-Related Factor 2/genetics*; NF-E2-Related Factor 2/metabolism; Phagosomes; Protein Isoforms/genetics; Protein Isoforms/metabolism; Sequestosome-1 Protein; Signal Transduction; Smoking; TOR Serine-Threonine Kinases/genetics; TOR Serine-Threonine Kinases/metabolism; Tobacco/chemistry*

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