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Live-Cell Lipid Biochemistry Reveals a Role of Diacylglycerol Side-Chain Composition for Cellular Lipid Dynamics and Protein Affinities

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Live-Cell Lipid Biochemistry Reveals a Role of Diacylglycerol Side-Chain Composition for Cellular Lipid Dynamics and Protein Affinities Live-cell lipid biochemistry reveals a role of diacylglycerol side-chain composition for cellular lipid dynamics and protein affinities Milena Schuhmachera, Andreas T. Grasskampb, Pavel Barahtjana, Nicolai Wagnera, Benoit Lombardota, Jan S. Schuhmachera, Pia Salac,d, Annett Lohmanna, Ian Henrya, Andrej Shevchenkoa, Ünal Coskunc,d, Alexander M. Walterb,1, and André Nadlera,1 aMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; bLeibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany; cPaul Langerhans Institute Dresden, Helmholtz Zentrum München, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; and dGerman Center for Diabetes Research, 85764 Neuherberg, Germany Edited by Satyajit Mayor, National Centre for Biological Sciences, Bangalore, India, and approved February 24, 2020 (received for review July 24, 2019) Every cell produces thousands of distinct lipid species, but insight (16) or the reciprocal regulation of ceramide species during Toll- into how lipid chemical diversity contributes to biological signaling like receptor signaling in innate immunity (17). DAGs appear to is lacking, particularly because of a scarcity of methods for quanti- be prime targets to study the importance of lipid heterogeneity in tatively studying lipid function in living cells. Using the example of cell signaling, as they act as second messengers at the plasma diacylglycerols, prominent second messengers, we here investigate membrane and function in many cellular processes, including in- whether lipid chemical diversity can provide a basis for cellular signal sulin signaling, ion channel regulation, and neurotransmitter release specification. We generated photo-caged lipid probes, which allow (18, 19). Many of these processes involve effector proteins such as acute manipulation of distinct diacylglycerol species in the plasma protein kinase C (PKC) isoforms, which are recruited to cellular membrane. Combining uncaging experiments with mathematical membranes by DAG binding to their C1 domains (20). Faithful modeling, we were able to determine binding constants for diacyl- glycerol–protein interactions, and kinetic parameters for diacylgly- process initiation thus requires the activation of a subset of DAG effector proteins in the presence of others as observed during the cerol transbilayer movement and turnover in quantitative live-cell BIOCHEMISTRY experiments. Strikingly, we find that affinities and kinetics vary by formation of the immunological synapse (21). However, the mo- orders of magnitude due to diacylglycerol side-chain composition. lecular mechanisms of such specific recruitment events are not well These differences are sufficient to explain differential recruitment understood. Here, specificity could be provided by differential acti- of diacylglycerol binding proteins and, thus, differing downstream vation of effectors by structurally distinct DAG species, which recruit phosphorylation patterns. Our approach represents a generally ap- specific DAG binding proteins due to differences in lipid-protein plicable method for elucidating the biological function of single lipid species on subcellular scales in quantitative live-cell experiments. Significance CHEMISTRY signaling lipids | diacylglycerol | protein kinase C | mathematical Every cell produces thousands of lipid species, but studying the modeling | caged lipid probes function of individual lipids in living cells is almost impossible with existing methodologies. Addressing this experimental bot- embrane lipids play a central role in cellular signal trans- tleneck, we developed a strategy to quantify dissociation con- Mduction. As receptor ligands, enzyme cofactors, and allo- stants for lipid–protein interactions and transmembrane flip-flop steric modulators, they control cellular excitability (1), immune rates of native lipids in live-cell experiments. Using a combination responses (2), cell migration (3, 4), and stem cell differentiation of plasma membrane-specific photochemical probes and mathe- (5, 6). In line with their fundamental importance, dysregulation matical modeling, we demonstrate that, for diacylglycerols as a of signaling lipids has been firmly established as a hallmark of model lipid class, the inherent lipid structural diversity caused by severe diseases such as cancer (7) and diabetes (8). Lipids are variations in acyl chain composition determines lipid protein af- grouped into classes characterized by common chemical fea- finities and transbilayer kinetics. In fact, subtle chemical differ- tures, such as their headgroup. Each of these classes comprises ences change these values by orders of magnitude. Our approach many molecularly distinct lipid species that differ in subtle represents a generally applicable method for elucidating the bi- chemical details, e.g., number of double bonds, ether or ester ological function of single lipid species on subcellular scales. linkages, as well as fatty acid chain length and positioning, ulti- mately suggesting the presence of thousands of individual lipid Author contributions: M.S., A.M.W., and A.N. designed research; M.S., A.T.G., P.B., N.W., species in mammalian cells (9, 10). While the heterogeneity of J.S.S., P.S., A.L., A.M.W., and A.N. performed research; M.S., A.T.G., B.L., I.H., and A.M.W. contributed new reagents/analytic tools; M.S., A.T.G., P.B., A.S., Ü.C., and A.N. analyzed the cellular lipidome in general and of signaling lipids in par- data; and M.S., A.T.G., A.M.W., and A.N. wrote the paper. ticular is well established, it is much less clear whether this The authors declare no competing interest. heterogeneity has causal relations to cellular function (11, 12). This article is a PNAS Direct Submission. Intriguingly, a growing body of evidence suggests that changes This open access article is distributed under Creative Commons Attribution-NonCommercial- in the levels of individual lipid species rather than entire lipid NoDerivatives License 4.0 (CC BY-NC-ND). classes determine cellular signaling outcome. For instance, early Data deposition: All software codes used for analysis have been deposited on the Max studies reported that activation of individual cell surface recep- Planck Institute of Molecular Cell Biology and Genetics repository, https://dx.doi.org/21. tors leads to the formation and degradation of distinct patterns 11101/0000-0007-DF4A-C. of diacylglycerol (DAG) species during signal transduction (13– See online for related content such as Commentaries. 15) on minute timescales. This suggests that crucial information 1To whom correspondence may be addressed. Email: [email protected] or nadler@ could be encoded in the molecular spectrum of generated sig- mpi-cbg.de. naling lipids. Supporting this notion, drastically altered levels of This article contains supporting information online at https://www.pnas.org/lookup/suppl/ distinct lipid species were correlated with cellular processes, e.g., doi:10.1073/pnas.1912684117/-/DCSupplemental. the increase of a phosphatidic acid ether lipid during cytokinesis First published March 25, 2020. www.pnas.org/cgi/doi/10.1073/pnas.1912684117 PNAS | April 7, 2020 | vol. 117 | no. 14 | 7729–7738 Downloaded by guest on September 27, 2021 affinities, local lipid densities, and lifetimes. Determining these uncaging and subsequent dissipation of the cleaved coumarin parameters requires quantitative experimental strategies that alcohol, whereas the fluorescence signal remained unchanged in allow perturbing and monitoring levels of native lipid species and endosomes (where the coumarin alcohol is trapped in the lumen) lipid–protein complexes in specific membranes of living cells. (Fig. 1F and Movie S1). By quantifying the observed fluores- However, such methods are not yet available (22). cence decreases at the plasma membrane and correcting for Closing this methodological gap, we developed chemical baseline fluorescence levels, we found very similar (on average probes for rapid, leaflet-specific ultraviolet (UV) uncaging of 66 ± 4%) uncaging efficiencies for all caged DAGs (Fig. 1G and individual DAG species at the plasma membrane of living cells. SI Appendix, Fig. S1-2 B–D and Extended Experimental Proce- This allowed temporally well-defined increases of native DAG dures). Since these experiments were done with a laser scanning species in a quantitative and dose-dependent fashion as a pre- microscope in a single plane, we also assessed whether the uncaging requisite for kinetic analysis. By combining DAG uncaging and changed throughout the cell in the z direction. To test this, we live-cell fluorescence imaging of DAG-binding proteins with acquired z-stacks of coumarin fluorescence before and after uncaging mathematical modeling, we demonstrate that 1) structural dif- at low laser intensity and found that the observed uncaging fluores- ferences between DAG species are sufficient to trigger different cence loss was very similar throughout the z-stack suggesting that recruitment patterns of various PKC isoforms and lead to dif- out of plane uncaging and/or rapid lateral diffusion of caged ferential phosphorylation of downstream signaling targets; 2) Kd DAGs contribute to near-homogenous DAG photo release (SI values of DAG–C1–domain interactions as well as transbilayer Appendix, Fig. S1-3). These settings were used for all uncaging movement and turnover rates differ by orders of magnitude experiments in this study unless stated otherwise (SI
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