Jeroen Demmers (1975) studied Chemistry at Utrecht University, the Netherlands. He earned his PhD degree from the same university in 2002, working on the development of tools to study interactions of transmembrane peptides and proteins with phospholipid bilayers using hydrogen-deuterium exchange and electrospray ionization mass spectrometry in the groups of Albert Heck and Antoinette Killian. During his postdoctoral studies in the group of Brian Chait at The Rockefeller University (New York) he worked on a project involving the proteomic identification of plasmid DNA binding proteins in yeast. In 2005, Jeroen moved to Erasmus Medical Center with an EUR Fellowship to initiate a mass spectrometry and proteomics facility and to set up a line of research in the field of protein mass spectrometry. Currently, he is an assistant professor of proteomics and his research focuses on the molecular mechanisms of the ubiquitin–proteasome system, for which he develops quantitative proteomics technologies that focus on the analysis of protein posttranslational modifications. Jeroen is head of the Erasmus MC proteomics core facility (see: Proteomics Center) and collaborates with many research groups within the institute and abroad on various topics such as protein-protein interactions, immunopeptidomics, targeted proteomics, etc. He is also a theme leader within the national Proteins@Work consortium and is a lecturer in the Nanobiology BSc and MSc education programs.
Selected publications (click here for complete list of publications).
- Van der Wal L, Bezstarosti K, Sap KA, Dekkers DHW, Rijkers E, Mientjes E, Elgersma Y, Demmers JAA (2018) Improvement of ubiquitylation site detection by Orbitrap mass spectrometry. J Proteomics 172:49-56.
- Sap KA, Bezstarosti K, Dekkers DHW, Voets O, Demmers JAA (2017) Quantitative Proteomics Reveals Extensive Changes in the Ubiquitinome after Perturbation of the Proteasome by Targeted dsRNA-Mediated Subunit Knockdown in Drosophila. J Proteome Res 16(8):2848-2862.
- Sap KA, Bezstarosti K, Dekkers DH, van den Hout M, van Ijcken W, Rijkers E, Demmers JAA (2015) Global quantitative proteomics reveals novel factors in the ecdysone signaling pathway in Drosophila melanogaster. Proteomics 15(4):725-38.
- V. Stalin Raj, Huihui Mou, Saskia L. Smits, Dick H. W. Dekkers, Marcel A. Müller, Ronald Dijkman, Doreen Muth, Jeroen A. A. Demmers, Ali Zaki, Ron A. M. Fouchier, Volker Thiel, Christian Drosten, Peter J. M. Rottier, Albert D. M. E. Osterhaus, Berend Jan Bosch & Bart L. Haagmans (2013) Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495:251–254.
- Twigt J, Steegers-Theunissen RP, Bezstarosti K, Demmers JAA (2012) Proteomic analysis of the microenvironment of developing oocytes. Proteomics 12(9):1463-71.
- Schwertman, P., Lagarou, A., Dekkers, D. H. W., Raams, A., van der Hoek, A. C., Laffeber, C., Hoeijmakers, J. H. J., Demmers, J. A. A., Fousteri, M., Vermeulen, W. & Marteijn, J. A. (2012) UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair. Nature Genetics 44:598-602.
- Adone Mohd-Sarip, Anna Lagarou, Ulku Aslan, Jan van der Knaap, Cecile Doyen, Karel Bezstarosti, Yasmin Yassin, Hugh W Brock, Jeroen AA Demmers & C. Peter Verrijzer (2012) Transcription-independent function of the Polycomb group protein PSC in cell cycle control. Science 336:744-747.
- Karel Bezstarosti, Alireza Ghamari, Frank G. Grosveld, Jeroen A. A. Demmers (2010) Differential proteomics based on 18O labeling to determine the Cyclin Dependent Kinase 9 interactome. J Proteome Res 9:4464-4475
- van den Berg DL, Snoek T, Mullin NP, Yates A, Bezstarosti K, Demmers J, Chambers I, Poot RA (2010) An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell 6:369-381.
The Demmers lab uses advanced proteomics, cell biological and biochemical approaches to study the ubiquitin-proteasome system (UPS). The UPS is a major process that includes the active marking of proteins by ubiquitin in order to be degraded. It is essential in the regulation of proteostasis in the cell; dysfunctioning of the UPS and proteome imbalance have been implicated in diseases such as cancer and neurodegenerative disorders. We are interested in dissecting the molecular mechanisms of the UPS. We manipulate the proteasome e.g. by depleting specific subunits and apply state-of-the-art quantitative proteomics technology to monitor the effects on the global proteome and the ubiquitinome. Research projects in the lab often have both a methodological and a biological angle. First, we develop analytical tools to better be able to study the proteome and ubiquitinome. These tools then allow us to study the molecular mechanism of the UPS and hence open up new avenues for the manipulation of the proteasome in UPS related diseases.
Remodeling of the ubiquitinome after proteasome inactivation
The ubiquitin-proteasome system (UPS) is a mechanism that includes the active marking of proteins by ubiquitin in order to be degraded. It is essential in the regulation of proteostasis in the cell. Dysfunctioning of the UPS has been implicated in diseases such as cancer and neurodegenerative disorders. We are interested in the effects of proteasome malfunctioning on the global proteome and the ubiquitinome, the complement of all ubiquitinated proteins in the cell.
To study this, we use SILAC proteomics in a cell system where we can manipulate the proteasome in a subtle way, i.e. by selective RNAi mediated knockdown of specific proteasome target subunits. Proteasome inactivation results in modification of the global proteome and especially the ubiquitinome: ubiquitinated proteins cannot be degraded anymore and are accumulated. Detailed study of 1000s of ubiquitination sites suggest the occurrence of simultaneous and perhaps functionally different ubiquitination events within single proteins.
This project has both a methodological and a biological angle. First, we develop analytical tools to better be able to study the ubiquitinome. Second, this strategy allows us to dissect the molecular mechanism of the UPS and hence opens up new avenues for the manipulation of the proteasome in UPS related diseases.
- Sap et al. (2017) J Proteome Res, doi: 10.1021/acs.jproteome.7b00156
- Van der Wal, Bezstarosti et al. (2018) J Proteomics, doi: 10.1016/j.jprot.2017.10.014
Development of tool for quantitative proteomics
We have optimized and implemented a method that uses 18O labeling of tryptic peptides to account for quantitative differences in protein levels between different samples. When all proteolytic peptides in e.g. a control sample are labeled with 18O, we can easily differentiate between real interactors of our protein of interest and non-specific background proteins in an interactomics experiment. We have successfully applied this method for quickly subtracting background proteins from real interactors in co-immunoprecipitation preparations.
Our lab also uses Stable Isotope Labeling of Amino acids in Cell culture (SILAC) for quantitative proteomics. In this approach, one sample originates from cells that were grown under normal conditions and the other sample is from cells that were grown in media containing amino acids that were labeled with heavy carbon (13C) and nitrogen (15N). One of our research projects involves investigation of changes in histone modifications after DNA damage and we use SILAC to identify and quantify such changes. If SILAC cannot be used isobaric tagging with Tandem Mass Tags (TMT) is a powerful alternative, especially because of the possibilities for multiplexing.
We are currently investigating the possibilities of targeted proteomics approaches such as Parallel Reaction Monitoring (PRM) to quantify target proteins in a label free manner and at very low concentrations in complex matrices. By spiking in heavy labeled peptides as concentration standards, PRM can even be used for absolute quantification (i.e., copy number per cell) of proteins.
- Sap et al. (2015) Proteomics 15(4):725-38
- Bezstarosti et al. (2010) J Proteome Res 9(9):4464-75