Abstract
Cigarette smoking plays an important role in increased incidence of chronic obstructive pulmonary disease (COPD). The underlying mechanism in which cigarette smoking induced impairment of lung epithelial cells is still unknown. SIRT5 is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, which has been implicated in the regulation of metabolism, stress responses, and aging. Forkhead box O3 (FOXO3) belongs to the O subclass of the forkhead family of transcription factors. It is also involved in protection from oxidative stress by upregulating antioxidants in epithelial cells. Here, we show that cigarette smoke extract (CSE) induces SIRT5 to deacetylate FOXO3 at K271 and K290. Deacetylation of FOXO3 promotes its nuclear localization. Notably, transfection with FOXO3 K271R- or K290R-attenuated CSE-induced apoptosis in SIRT5 knocked down cells, suggesting the protective effects of SIRT5, is mediated by FOXO3. In contrast, CSE stress upregulates SIRT5, which activates FOXO3α leading to rescuing apoptosis. Thus, SIRT5 constitutes a determinant of apoptosis by CSE in lung epithelial cells.
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References
Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y et al (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015
Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27:2276–2288
Caramori G, Adcock IM, Di Stefano A, Chung KF (2014) Cytokine inhibition in the treatment of COPD. Int J Chron Obstruct Pulmon Dis 9:397–412
Chun P (2015) Role of sirtuins in chronic obstructive pulmonary disease. Arch Pharm Res 38(1):1–10
Du J, Zhou Y, Su X, Yu JJ, Khan S et al (2011) Sirt5 is a NAD-dependent protein lysinedemalonylase and desuccinylase. Science 334(6057):806–9
Frescas D, Valenti L, Accili D (2005) Nuclear trapping of the forkhead transcription factor FoxO1via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 280:20589–20595
Jacobs KM, Pennington JD, Bisht KS, Aykin-Burns N, Kim HS, Mishra M et al (2008) SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression. Int J Biol Sci 4:291–299
Kode A, Yang SR, Rahman I (2006) Differential effects of cigarette smoke on oxidative stress and proinflammatory cytokine release in primary human airway epithelial cells and in a variety of transformed alveolar epithelial cells. Respir Res 7:132
Lan MY, Ho CY, Lee TC et al (2007) Cigarette smoke extract induces cytotoxicity on human nasal epithelial cells. Am J Rhinol 21:218–223
Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRTproteins. Mol Biol Cell 16(10):4623–35
Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C (2008) Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol 382(3):790–801
Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, Zhu X (2012) Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease. J Neurochem 120(3):419–29
Su Y, Han W, Giraldo C, De Li Y, Block ER (1998) Effect of cigarette smoke extract on nitric oxide synthase in pulmonary artery endothelial cells. Am J Respir Cell Mol Biol 19:819–825
Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP (2009) Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 119:2758–2771
Togo S, Sugiura H, Nelson A et al (2010) Hepatic growth factor (HGF) inhibits cigarette smoke extract induced apoptosis in human bronchial epithelial cells. Exp Cell Res 316:3501–3511
Van der Horst A, Burgering BM (2007) Stressing the role of FoxO proteins in life span and disease. Nat Rev Mol Cell Biol 8:440–450
Verdin E, Hirschey MD, Finley LWS, Haigis MC (2010) Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 35:669–675
Vogt PK, Jiang H, Aoki M (2005) Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins. Cell Cycle 4:908–913
Wang F, Nguyen M, Qin FX, Tong Q (2007) SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell 6:505–514
Wu CH, Lin HH, Yan FP, Wu CH, Wang CJ (2006) Immunohistochemical detection of apoptotic proteins, p53/Bax and JNK/FasL cascade, in the lung of rats exposed to cigarette smoke. Arch Toxicol 80:328–336
Yao H, Sundar IK, Ahmad T, Lerner C, Gerloff J, Friedman AE, Phipps RP, Sime PJ, McBurney MW, Guarente L, Rahman I (2014) SIRT1 protects against cigarette smoke-induced lung oxidative stress via a FOXO3-dependent mechanism. Am J Physiol Lung Cell Mol Physiol 306(9):L816–28
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Wang, Y., Zhu, Y., Xing, S. et al. SIRT5 prevents cigarette smoke extract-induced apoptosis in lung epithelial cells via deacetylation of FOXO3 . Cell Stress and Chaperones 20, 805–810 (2015). https://doi.org/10.1007/s12192-015-0599-7
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DOI: https://doi.org/10.1007/s12192-015-0599-7