Abstract
SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.
Highlights
Sirtuins are nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, which are originally found as the human homologs of silent information regulator 2 (Sir2) genes in Saccharomyces cerevisiae [1]
As BEAS-2B cell line is an immortalized bronchial epithelial cell line, we investigated the localization of SIRT1 in human primary airway epithelial cells of bronchial origin in monolayer culture and air-liquid interface (ALI)-cultured human bronchial epithelial cell (HBEC)
SIRT1 was found within the nucleus in human pulmonary artery endothelial cells, suggesting that the distribution of SIRT1 differed from one cell type to another as previously reported [22,24]
Summary
Sirtuins are nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, which are originally found as the human homologs of silent information regulator 2 (Sir2) genes in Saccharomyces cerevisiae [1]. Seven isoforms of sirtuins have been identified in human (SIRT1-SIRT7) [2]. Through their different intracellular distribution [3] and specificity toward diverse acetylated substance proteins [4,5,6], sirtuins are known to regulate various cellular processes such as apoptosis, cellular senescence, endocrine signaling, glucose homeostasis and aging [7,8]; most of which are built on the delicate balances between oxidative vs anti-oxidative. SIRT1 nuclear shuttling by cigarette smoke collection and analysis, decision to publish, or preparation of the manuscript. Pulmocide Ltd provided support in the form of salaries for authors [KI, TC], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript
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