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Modulation of host cell membrane dynamics during infection

Tuesday 23 October 2012

Prof. dr. J.B. (Bernd) Helms
Chairman of Department of Biochemistry and Cell Biology
Director of the Institute of Biomembranes

Research over the last decades has identified a crucial role of lipids in cellular signaling, membrane microdomain organization, membrane dynamics, and membrane trafficking. Thus, lipids play a crucial role in various cellular processes which makes them attractive targets for pathogens to modulate host cell processes allowing their survival and replication. Pathogens have devised ingenious strategies to modify lipid homeostasis of host cells, allowing them to divert cellular processes. To this end pathogens take full advantage of the complexity of the lipidome: current estimates indicate that mammalian cells have 10.000-100.000 different lipid species. This number suggests that lipids are ideally suited for modulation of host cell dynamics.

To investigate host cell factors that are involved in modulating lipid membrane dynamics during infection we are currently following up on two lines of research:

I. Modulation of host cell membrane dynamics by Salmonella Typhimurium
To investigate the interaction of Salmonella with the host cell we developed a SILAC-based quantitative proteomics analysis and identified 105 host-cell proteins that were affected upon Salmonella infection and started a systematic screen for the function of these proteins in host-pathogen interactions. Investigations of these proteins allowed us to identify two different Salmonella entry pathways. We currently investigate the different lipid requirements for the two pathways. We also study the interaction of two specific Salmonella effector proteins, SseG and SrfJ with host cell factors. The effector protein SseG is important for Salmonella replication and it is necessary for the Golgi localization of the pathogenic vacuole. SrfJ is a Salmonella effector which shows high sequence similarity to human lysosomal lipid hydrolase. We want to elucidate the activity of SrfJ and its role during Salmonella infection.

II. Modulation of membrane dynamics by GAPR-1
We characterized a previously unknown protein named GAPR-1. GAPR-1 belongs to the superfamily of plant pathogenesis-related (PR-1) proteins that play an essential role in the defence of plants. The plant defence system is reminiscent of the innate immune system in mammals. Thus, investigations on GAPR-1 in mammals will have broad implications for all kingdoms of life. We found evidence for very dynamic interactions of GAPR-1 with membrane lipids, allowing regulation of the oligomeric properties, revealing a novel function of lipids. Our current research is aimed at investigating the relevance of protein-lipid interactions for the biological function of GAPR-1 in innate immunity. Our recent identification of the involvement of GAPR-1 in autophagy strongly supports this notion.

Key Interests
Innate Immunity; Host-pathogen interactions; membrane dynamics; Salmonella; Lipids; Phagocytosis; GAPR-1; CAP superfamily of proteins.

Yeast two hybrid, Co-Immunoprecipitation, cloning, cell culture, Salmonella infection experiments, RNA interference, fluorescence microscopy, protein expression and purification, enzymatic assays, lipid mass spectrometry

Current research group
Bernd Helms, professor in Biochemistry
Dora Kaloyanova, assistant professor
Nick Olrichs, Post-Doc
Ignace de Ruijter, PhD student
Ruud Eerland, Technician

Website Research Group
CV Principle Investigator

Key papers:
Shoji-Kawata, S., Sumpter, R., Leveno, M., Campell, G.R., Zou, Z., Kinch, L., Wilkins, A.D., Sun, Q., Pallauf, K., MacDuff, D., Huerta, C., Virgin, H.W., Helms, J.B., Eerland, R., Tooze, S.A., Xavier, R., Lenschow, D.J., Yamamoto, A., King, D., Lichtarge, O., Grishin, N.V., Spector, S.A., Kaloyanova, D.V., and Beth Levine. Identification of a candidate therapeutic autophagy-inducing peptide (2013) Nature 494, 201-206

Alejandro O. Sodero, Joris Vriens, Debapriya Ghosh, David Stegner, Marta Pallotto, Marco Sassoè-Pognetto, Bernhard Nieswandt, Jos Brouwers, Bernd Helms Thomas Voets and Carlos G. Dotti Cholesterol loss during glutamate-mediated excitotoxicity (2012) EMBO J. 31, 1764 - 1773

Cebollero, E., van der Vaart, A., Zhao, M., Rieter, E., Klionsky, D.J., Helms, J.B., and Reggiori, F. Phosphatidylinositol-3-phosphate clearance plays a key role in autophagosome completion (2012) Current Biol. 22, 1545-1553

Testerink, M., Ajat, M.A., Houweling, M., Brouwers, J.F., Pully, V.V., van Manen, H-J., Otto, C., Helms, J.B., and Vaandrager, A.B. Replacement of retinyl esters by polyunsaturated triacylglycerol species in lipid droplets of hepatic stellate cells during activation (2012) PLoS ONE 7, e34945

Vogels, M.W., van Balkom, B.W.M., Heck, A.J., de Haan, C.A.M., Rottier, P.J.M., , Batenburg, J.J., Kaloyanova, D.V., Helms, J.B. Quantitative proteomic identification of host factors involved in the Salmonella typhimurium infection cycle (2011) Proteomics 11, 4477-4491

Van Galen, J., Olrichs, N., Schouten, A., Serrano, R.L., Note-'t Hoen, E., Eerland, R., Kaloyanova, D., Gros, P. and J. Bernd Helms. Interaction of GAPR-1 with lipid bilayers is regulated by alternative homodimerization BBA-Biomembranes 1818 (2012) 21752183

Vogels, M.W., van Balkom, B.W.M., Kaloyanova, D.V., Batenburg, J.J., Heck, A.J., Helms, J.B., Rottier, P.J.M., de Haan, C.A.M. Identification of host factors involved in coronavirus replication by quantitative proteomic analysis (2011) Proteomics 11, 64-80.

Van der Meer-Janssen, Y.P.M., van Galen, J., Batenburg, J.J., and Helms, J.B. Lipids in host-pathogen interactions: pathogens exploit the complexity of the host cell lipidome (2010) Prog. Lipid Res. 49, 1-26

Li, X., Kaloyanova, D., van Eijk, M., Eerland, R., van der Goot, G., Oorschot, V., Klumperman, J., Lottspeich, F., Starkuviene, V., Wieland, F.T., and Helms, J.B. (2007) Involvement of a GPI-anchored Protein in Maintenance of the Golgi Structure Mol. Biol. Cell 18, 1261-1271.

Serrano, R.L., Kuhn A., Hendricks A., Helms J.B., Sinning I., and Groves M.R. Structural analysis of the human Golgi-associated plant pathogenesis related protein GAPR-1 implicates dimerization as a regulatory mechanism (2004) J. Mol. Biol. 339, 173-183.

Helms, J.B. and Zurzolo, C. Lipids as targeting signals: lipid rafts and intracellular trafficking (2004) Traffic 5, 247-254.

Stüven, E., Porat, A., Shimron, F., Fass, E., Kaloyanova, D., Brügger, B., Wieland, F.T., Elazar, Z. and Helms, J.B. Intra-Golgi protein transport depends on a cholesterol balance in the lipid membrane (2003) J. Biol. Chem. 278, 53112-53122.

Eberle, H.B., Serrano, R.L., Füllekrug, J., Schlosser, M., Lehmann, W.D., Lottspeich, F., Kaloyanova, D., Wieland, F.T., and Helms, J.B. Identification and characterization of a novel human plant pathogenesis-related protein that localizes to lipid-enriched microdomains in the Golgi complex (2002) J. Cell Sci. 115, 827-838.