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Edited by David M. Chenoweth, University of Pennsylvania, Philadelphia, PA, and accepted by Editorial Board Member Stephen J. Benkovic June 13, 2018 (received for review March 11, 2018)
Significance
Ceramides are a chemically diverse class of sphingolipids that have critical roles in a wide range of biological pathways. Despite their high biological interest, ceramides have been difficult to study because of their impermeability to the cell membrane. We overcome the principal issues with ceramide delivery by chemoselectively ligating lipid precursors in vivo. Our method employs a proximity-induced ligation which allows for the in situ synthesis of several different natural ceramide species within live cells. Using this approach, we directly confirm the proapoptotic effects of C16:0 ceramide in vivo and observe that ceramide saturation plays a determinant role in ceramide-driven apoptosis.
Abstract
Mammalian cells synthesize thousands of distinct lipids, yet the function of many of these lipid species is unknown. Ceramides, a class of sphingolipid, are implicated in several cell-signaling pathways but poor cell permeability and lack of selectivity in endogenous synthesis pathways have hampered direct study of their effects. Here we report a strategy that overcomes the inherent biological limitations of ceramide delivery by chemoselectively ligating lipid precursors in vivo to yield natural ceramides in a traceless manner. Using this method, we uncovered the apoptotic effects of several ceramide species and observed differences in their apoptotic activity based on acyl-chain saturation. Additionally, we demonstrate spatiotemporally controlled ceramide synthesis in live cells through photoinitiated lipid ligation. Our in situ lipid ligation approach addresses the long-standing problem of lipid-specific delivery and enables the direct study of unique ceramide species in live cells.
Footnotes
- ↵1To whom correspondence should be addressed. Email: ndevaraj{at}ucsd.edu.
Author contributions: A.K.R. and N.K.D. designed research; A.K.R. performed research; A.K.R. analyzed data; and A.K.R. and N.K.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. D.M.C. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1804266115/-/DCSupplemental.
Published under the PNAS license.
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Traceless synthesis of ceramides in living cells reveals saturation-dependent apoptotic effects
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