LSD1-S112A exacerbates the pathogenesis of CSE/LPS-induced chronic obstructive pulmonary disease in mice
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Lysine-specific demethylase 1 (LSD1) is an epigenetic regulator that modulates the chromatin status, contributing to gene activation or repression. The post-translational modification of LSD1 is critical for the regulation of many of its biological processes. Phosphorylation of serine 112 of LSD1 by protein kinase C alpha (PKCα) is crucial for regulating inflammation, but its physiological significance is not fully understood. This study aimed to investigate the role of Lsd1-S112A, a phosphorylation defective mutant, in the cigarette smoke extract/LPS-induced chronic obstructive pulmonary disease (COPD) model using Lsd1SA/SA mice and to explore the potential mechanism underpinning the development of COPD. We found that Lsd1SA/SA mice exhibited increased susceptibility to CSE/LPS-induced COPD, including high inflammatory cell influx into the bronchoalveolar lavage fluid and airspace enlargement. Additionally, the high gene expression associated with the inflammatory response and oxidative stress was observed in cells and mice containing Lsd1-S112A. Similar results were obtained from the mouse embryonic fibroblasts exposed to a PKCα inhibitor, Go6976. Thus, the lack of LSD1 phosphorylation exacerbates CSE/LPS-induced COPD by elevating inflammation and oxidative stress.
Abstract
Lysine-specific demethylase 1 (LSD1) is an epigenetic regulator that modulates the chromatin status, contributing to gene activation or repression. The post-translational modification of LSD1 is critical for the regulation of many of its biological processes. Phosphorylation of serine 112 of LSD1 by protein kinase C alpha (PKCα) is crucial for regulating inflammation, but its physiological significance is not fully understood. This study aimed to investigate the role of Lsd1-S112A, a phosphorylation defective mutant, in the cigarette smoke extract/LPS-induced chronic obstructive pulmonary disease (COPD) model using Lsd1SA/SA mice and to explore the potential mechanism underpinning the development of COPD. We found that Lsd1SA/SA mice exhibited increased susceptibility to CSE/LPS-induced COPD, including high inflammatory cell influx into the bronchoalveolar lavage fluid and airspace enlargement. Additionally, the high gene expression associated with the inflammatory response and oxidative stress was observed in cells and mice containing Lsd1-S112A. Similar results were obtained from the mouse embryonic fibroblasts exposed to a PKCα inhibitor, Go6976. Thus, the lack of LSD1 phosphorylation exacerbates CSE/LPS-induced COPD by elevating inflammation and oxidative stress.
참고문헌 (30)
- Corlateanu A, "Chronic obstructive pulmonary disease and phenotypes : a state-ofthe-art", Pulmonology, 26, pp.95~100 (2020)
- Sundar IK, "Gene expression profiling of epigenetic chromatin modification enzymes and histone marks by cigarette smoke : implications for COPD and lung cancer", Am J Physiol Lung Cell Mol Physiol, 311, pp.L1245~L1258 (2016)
- Ito K, "Decreased histone deacetylase activity in chronic obstructive pulmonary disease", N Engl J Med, 352, pp.1967~1976 (2005)
- Nakamaru Y, "A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9", FASEB J, 23, pp.2810~2819 (2009)
- Sundar IK, "Cigarette smoke induces distinct histone modifications in lung cells : Implications for the pathogenesis of COPD and lung cancer", J Proteome Res, 13, pp.982~996 (2014)
- Stepaniants S, "Genes related to emphysema are enriched for ubiquitination pathways", BMC Pulm Med, 14, pp.187~ (2014)
- Liu W, "The deubiquitinase USP38 affects cellular functions through interacting with LSD1", Biol Res, 51, pp.53~ (2018)
- Forneris F, "Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process", FEBS Lett, 579, pp.2203~2207 (2005)
- Shi Y, "Histone demethylation mediated by the nuclear amine oxidase homolog LSD1", Cell, 119, pp.941~953 (2004)
- Maiques-Diaz A, "LSD1 : biologic roles and therapeutic targeting", Epigenomics, 8, pp.1103~ (2016)
- Amente S, "The histone LSD1demethylase in stemness and cancer transcription programs", Biochim Biophys Acta, 1829, pp.981~986 (2013)
- Nam HJ, "Phosphorylation of LSD1 by PKCα is crucial for circadian rhythmicity and phase resetting", Mol Cell, 53, pp.791~805 (2014)
- Peng B, "Phosphorylation of LSD1 by PLK1 promotes its chromatin release during mitosis", Cell Biosci, 7, pp.15~ (2017)
- Peng B, "Modulation of LSD1phosphorylation by CK2", WIP1 regulates RNF168-dependent 53BP1 recruitment in response to DNA damage, 2015, pp.43, 5936~5947
- Kim D, "PKCα-LSD1-NF-κBsignaling cascade is crucial for epigenetic control of the inflammatory response", Mol Cell, 69, pp.398~411 (2018)
- Tsai CL, "Stress-induced phosphoprotein 1 acts as a scaffold protein for glycogen synthase kinase-3β-mediated phosphorylation of lysinespecific demethylase 1", Oncogenesis, 7, pp.31~ (2018)
- Lim CS, "PKCα-mediated phosphorylation of LSD1 is required for presynaptic plasticity and hippocampal learning and memory", Sci Rep, 7, pp.4912~ (2017)
- Feng J, "Phosphorylation of LSD1 at Ser112 is crucial for its function in induction of EMT and metastasis in breast cancer", Breast Cancer Res Treat, 159, pp.443~456 (2016)
- 오채윤, "Inhibition of LSD1 phosphorylation alleviates colitis symptoms induced by dextran sulfate sodium", BMB Reports, 53(7), pp.385~390 (2020), 생화학분자생물학회[DOI]
- Naito M, "Thrombinactivatable fibrinolysis inhibitor protects against acute lung injury by inhibiting the complement system", Am J Respir Cell Mol Biol, 49, pp.646~653 (2013)
- Strzelak A, "Tobacco smoke induces and alters immune responses in the lung triggering inflammation, allergy, asthma and other lung diseases : a mechanistic review", Int J Environ Res Public Health, 15, pp.1033~ (2018)
- Yu D, "Isoliquiritigenin inhibits cigarette smoke-induced COPD by attenuating inflammation and oxidative stress via the regulation of the Nrf2and NF-κB signaling pathways", Front Pharmacol, 9, pp.1001~ (2018)
- Zarkovic N, "4-Hydroxynonenal as a bioactive marker of pathophysiological processes", Mol Aspects Med, 24, pp.281~291 (2003)
- Ayala A, "Lipid peroxidation : production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal", Oxid Med Cell Longev, 2014, pp.360438~ (2014)
- Churg A, "Acute cigarette smoke–induced connective tissue breakdown requires both neutrophils and macrophage metalloelastase in mice", Am J Respir Cell Mol Biol, 27, pp.368~374 (2002)
- Rahman I, "4-Hydroxy-2-nonenal, a specific lipid peroxidation product, is elevated in lungs of patients with chronic obstructive pulmonary disease", Am J Respir Crit Care Med, 166, pp.490~495 (2002)
- Gaschler MM, "Lipid peroxidation in cell death", Biochem Biophys Res Commun, 482, pp.419~425 (2017)
- Pezone A, "Targeted DNA oxidation by LSD1-SMAD2", 3 primes TGF-β1, Nucleic Acids Res, pp.2020, 48[DOI]
- Duquette ML, "LSD1 mediated changes in the local redox environment during the DNA damage response", PLoS One, 13, pp.e0201907~ (2018)
- Braber S, "Inflammatory changes in the airways of mice caused by cigarette smoke exposure are only partially reversed after smoking cessation", Respir Res, 11, pp.99~ (2010)