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Nuclear Sphingosine-1-phosphate Lyase Generated ∆2-hexadecenal is A Regulator of HDAC Activity and Chromatin Remodeling in Lung Epithelial Cells

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Abstract

Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, is generated from sphingosine by sphingosine kinases (SPHKs) 1 and 2 and is metabolized to ∆2-hexadecenal (∆2-HDE) and ethanolamine phosphate by S1P lyase (S1PL) in mammalian cells. We have recently demonstrated the activation of nuclear SPHK2 and the generation of S1P in the nucleus of lung epithelial cells exposed to Pseudomonas aeruginosa. Here, we have investigated the nuclear localization of S1PL and the role of 2-HDE generated from S1P in the nucleus as a modulator of histone deacetylase (HDAC) activity and histone acetylation. Electron micrographs of the nuclear fractions isolated from MLE-12 cells showed nuclei free of ER contamination, and S1PL activity was detected in nuclear fractions isolated from primary lung bronchial epithelial cells and alveolar epithelial MLE-12 cells. Pseudomonas aeruginosa-mediated nuclear ∆2-HDE generation, and H3/H4 histone acetylation was attenuated by S1PL inhibitors in MLE-12 cells and human bronchial epithelial cells. In vitro, the addition of exogenous ∆2-HDE (100–10,000 nM) to lung epithelial cell nuclear preparations inhibited HDAC1/2 activity, and increased acetylation of Histone H3 and H4, whereas similar concentrations of S1P did not show a significant change. In addition, incubation of ∆2-HDE with rHDAC1 generated five different amino acid adducts as detected by LC-MS/MS; the predominant adduct being ∆2-HDE with lysine residues of HDAC1. Together, these data show an important role for the nuclear S1PL-derived ∆2-HDE in the modification of HDAC activity, histone acetylation, and chromatin remodeling in lung epithelial cells.

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All data presented and discussed are contained within the manuscript. All the data and materials are available from V.N.

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Acknowledgements

The P. aeruginosa 103 strain stock culture was provided by Dr. Ruxana T. Sadikot during her tenure at University of Illinois, Chicago. This work made use of the instrumentation provided by the Electron Microscopy Core of the University of Illinois at Chicago’s Research Resources Center. We thank Ms. Figen A. Seiler, M.S. for her excellent services at the UIC Electron Microscopy Core for processing the Transmission Electron Micrographs.

Authors' Contributions

Conceptualization—D.L.E., V.N., and B.K.; Methodology—D.L.E., R.R., P.F.U., V.N., A.W.H., L.A.M., P.P.K.K., E.V.B., and F.S.; Formal analysis—D.L.E., P.P.K.K., R.R., E.V.B., and V.N.; Investigation—D.L.E., V.N., B.K., and F.S.; Resources—V.N., B.K., P.P.V.V., and S.J.K.; Writing (Review and editing)—R.R. and V.N.; Project administration—V.N.; Funding acquisition—V.N. and S.J.K.

Funding

This work was supported by National Institutes of Health grants HLBI P01HL126609, P01HL060678, R01HL127342 (to VN), and R01 AG069865 (to S.J.K.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence to Viswanathan Natarajan.

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Ebenezer, D.L., Ramchandran, R., Fu, P. et al. Nuclear Sphingosine-1-phosphate Lyase Generated ∆2-hexadecenal is A Regulator of HDAC Activity and Chromatin Remodeling in Lung Epithelial Cells. Cell Biochem Biophys 79, 575–592 (2021). https://doi.org/10.1007/s12013-021-01005-9

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