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

Lingxiang Zhu, Erika C. Barret, Yuxue Xu, Zuguo Liu, Aditya Manoharan, Yin Chen

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere55695
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 9 2013

Fingerprint

autophagy
cigarettes
Autophagy
smoke
Smoke
Tobacco Products
Chemical activation
extracts
Pulmonary diseases
Starvation
Cell death
Epithelial Cells
starvation
epithelial cells
Genes
Chronic Obstructive Pulmonary Disease
respiratory tract diseases
Autophagosomes
genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Zhu, L., Barret, E. C., Xu, Y., Liu, Z., Manoharan, A., & Chen, Y. (2013). Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2. PLoS One, 8(4), [e55695]. https://doi.org/10.1371/journal.pone.0055695

Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2. / Zhu, Lingxiang; Barret, Erika C.; Xu, Yuxue; Liu, Zuguo; Manoharan, Aditya; Chen, Yin.

In: PLoS One, Vol. 8, No. 4, e55695, 09.04.2013.

Research output: Contribution to journalArticle

Zhu, L, Barret, EC, Xu, Y, Liu, Z, Manoharan, A & Chen, Y 2013, 'Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2', PLoS One, vol. 8, no. 4, e55695. https://doi.org/10.1371/journal.pone.0055695
Zhu, Lingxiang ; Barret, Erika C. ; Xu, Yuxue ; Liu, Zuguo ; Manoharan, Aditya ; Chen, Yin. / Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2. In: PLoS One. 2013 ; Vol. 8, No. 4.
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