Our group is interested in unravelling the mechanisms behind lipid-mediated signalling events. Certain lipid species, especially ones belonging to the biologically active sphingolipids, are powerful signalling molecules involved in many central processes. Therefore, cells must exert tight control over signalling lipid levels. One control checkpoint is the lysosome; an organelle responsible for the breakdown of cellular material such as proteins, nucleic acid, carbohydrates and lipids. Specifically, many sphingolipid degrading enzymes are localized in the lysosome and any malfunction in this catabolic cascade leads to devastating pathologies. As many mechanisms of lysosomal lipid homeostasis are still unknown, we are interested in studying the lysosome in general and its role in lipid-mediated signalling in particular.
For example, we are pursuing the following questions:
I. What are the protein effectors of signalling lipids?
We have recently developed novel chemical biology tools which allow the identification of protein interactors of single lipid species and plan to further develop this technology. Applied to disease-relevant lipids such as sphingosine, we hope to gain insight into the mechanisms of lipid-mediated signalling and potentially identify new avenues for treatment.
II. How is lipid transport organized?
It is still unclear how the removal or reuse of the breakdown products upon degradation of complex lipids by lysosomal catabolic enzymes is coordinated. By directly visualizing lipid transport from the lysosome, we aim to uncover the mechanisms responsible for establishing and maintaining routes for lysosomal lipid export.
To achieve these goals, we develop and employ novel chemical biology tools complemented with cell biology studies in mammalian cells. Using lysosomal storage diseases as models, we aim to uncover novel pathways and to advance the concept of the lysosome as a signalling hub.
Harwig P, Höglinger D (2021) The glucosylceramide synthase inhibitor PDMP causes lysosomal lipid accumulation and mTOR inactivation. Int J Mol Sci, 22(13):7065 doi:10.3390/ijms22137065
Schoop V, Martello A, Eden ER, Höglinger D (2021) Cellular cholesterol and how to find it. BBA Mol Cell Biol Lipids, 1866(9):158989 doi:10.1016/j.bbalip.2021.158989
Höglinger D, Burgoyne T, Sanchez-Heras E, Hartwig P, Colaco A, Newton J, Futter C, Spiegel S, Platt F, Eden E. (2019). NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress. Nat Commun, 10(1):4276, doi: 10.1038/s41467-019-12152-2.
Höglinger D. (2019) Bi- and Trifunctional Lipids for Visualization of Sphingolipid Dynamics within the Cell. Methods Mol Biol, 1949:95-103, doi: 10.1007/978-1-4939-9136-5_8.
Wagner N, Stephan M, Höglinger D, Nadler A. (2018) A click cage: Organelle-specific uncaging of lipid mes-sengers. Angew Chem Int Ed Engl, 57: 1-6, doi: 10.1002/anie.201807497
Höglinger D, Nadler A, Haberkant P, Kirkpatrick J, Schifferer M, Stein F, Hauke S, Porter FD, Schultz C. Trifunctional lipid probes for comprehensive studies of single lipid species in living cells.
PNAS 2017; 114; 7; 1566-1571; doi: 10.1073/pnas.1611096114
Fineran P, Lloyd-Evans E, Lack NA, Platt N, Davis LC, Morgan AJ, Höglinger D, Tatituri RV, Clark S, Williams IM, Tynan P, Al Eisa N, Nazarova E, Willians A, Galione A, Ory DS, Besra GS, Russell DG, Brenner MB, Sim E, Platt FM. Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway
. Wellcome Open Res 2016; 1;18; doi: 10.12688/wellcomeopenres.10036.1.
Haberkant P, Stein F, Höglinger D, Gerl MJ, Brügger B, Van Veldhoven PP, Krijgsveld J, Gavin AC, Schultz C. Bifunctional sphingosine for cell-based analysis of proteins-sphingolipid interactions
. ACS Chem Biol 2016; 11; 222-230
Höglinger D, Haberkant P, Aguilera-Romero A, Riezman H, Porter FD, Platt FM, Galione A, Schultz C. Intracellular sphingosine releases calcium from lysosomes
. ELife 2015
; doi: 10.7554/eLife.10616
Höglinger D, Nadler A, Schultz C. Caged lipids as tools for investigating cellular signaling
. Biochim Biophys Acta 2014; 1841; 1085-1096