Timo Burster
Timo Burster, Habil., PhD, Immunology
1. Degrees and education
11/10
Teaching qualification: Venia legendi (Habilitation) in Experimental Medicine, University Medical Center Ulm, Germany
03/04 to 03/06
Postdoctoral Research Fellow, Stanford University School of Medicine, Stanford, CA, USA
01/01 to 12/03
Ph.D., Immunology, University of Tübingen, Germany
1997 to 2000
M.S. (Diplom) in Biology, University of Tübingen, Germany
1993 to 1997
B.S. (Vordiplom) in Biology, University of Freiburg, Germany
2. Research experience and previous employment
01/18 to present
Associate Professor, Dept. Biology, School of Science and Technology, Nazarbayev University, Astana, Kazakhstan, Immunology, Tumor Immunology, Biochemistry
09/13 to 12/17
Laboratory Head, Principle Investigator, Dept. Neurosurgery, Ulm University Medical Centre, Ulm, Germany, Tumor Immunology
11/13 to 09/16
Visiting Professor, Humboldt Award, Poland/Germany, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland, Immunology, Immunosenescence
10/12 to 06/13
Visiting Professor, Dept. Chemistry, University of Gdansk, Gdansk, Poland and Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland, stipend DAAD, Immunology
07/11 to present
Extraordinary Member of the University Medical Center Ulm (Habilitation, Privatdozent), Ulm University, Ulm, Germany, Immunology, Biochemistry
10/06 to 06/11
Team Leader, Dept. Internal Medicine I, University Medical Center Ulm, Ulm, Germany, Autoimmunity
03/04 to 03/06
Postdoctoral Research Fellow, stipend DFG, Division of Pediatric Immunology and Transplantation Medicine, Stanford University School of Medicine, Stanford, CA, USA, Immunology, Biochemistry
01/01 to 12/03
Ph.D., Medical and Natural Sciences Research Center (MNF), University of Tübingen, Tübingen, Germany, Immunology, Autoimmunity
05/00 to 12/00
M.S. (Diplom) in Biology, Medical and Natural Sciences Research Center (MNF), University of Tübingen, Tübingen, Germany, Immunology
12/98 to 03/00
Scientific Assistant Max-Planck-Institute for Developmental Biology (MPI), Tübingen, Germany, Axon guidance
3. Lectures
Spring 2020:
BIOL 341 Biochemistry I and Recitation
BIOL 341 Biochemistry Laboratory
BIOL 410 Introduction to Immunology
Fall 2019:
BIOL 341 Biochemistry I and Recitation
BIOL 410 Introduction to Immunology
Spring 2019:
BIOL 341 Biochemistry I and Recitation
BIOL 341 Biochemistry Laboratory
BIOL 480 Molecular Immunology
Fall 2018:
BIOL 410 Introduction to Immunology
BIOL 623 Advanced Immunology
Spring 2018:
BIOL 341 Biochemistry I and Recitation
4. Description of research activities
Functional responsibilities of cathepsin G (CatG) in immunity, including bivalent regulation of major histocompatibility complex class I (MHC) molecules, which underscore a novel role of CatG within the immune system. Special Interests: Immune evasion of tumor cells and pathogens, modulating of the proteolytic activity of CatG, functional properties of CatG in T cells.
Our model of how exogenous CatG modulates cell surface expression of MHC I: CatG proteolytically cleaves the N-terminal end of the extracellular domain of protease-activated receptor 1 (PAR1). As a result, the tethered activation ligand flips to the extracellular loop 2 and recruits intracellular G protein, which is capable of downstream signal transduction. However, cleavage of the extracellular part of PAR1 by CatG can also lead to receptor inactivation, so-called dis-arming; thereby the tethered ligand as well as three extracellular loops of PAR1 are digested and blocks G protein-mediated signaling. This can be further enhanced by the interaction of lactoferrin (LF) with CatG. LF increases the proteolytic activity of CatG and augments a CatG-mediated upregulation of MHC I molecules on the cell surface. The MHC I recycling pathway, for instance, is important for loading a new set of antigenic peptides (viral derived or tumor-associated) to MHC I molecules in order to be displayed on the cell surface for CD8+ T cell inspection. Distinct viruses or tumor cells prevent the synthesis of nascent MHC I molecules or interfere with the MHC I recycling pathway. The advantage of CatG-mediated upregulation of cell surface MHC I molecules is the efficacy to reuse MHC I within the MHC I recycling pathway, where MHC I molecules are pushed out to the cell surface instead of being degraded in the lysosome, as an additional model regarding how CatG circumvents immune evasion of viruses or tumor cells.
4.1. Immunosenescence
Aging is associated with a decreased functional immune response known as immunosenescence. Increased susceptibility to autoimmunity, neurodegeneration, infectious diseases, cardiovascular pathologies, and cancer is found in elderly persons resulting in higher mortality. Although aged-related immunity is declined, high levels of cytokines, increased inflammation, and imbalanced protease-activity are found in elderly persons, which on the downside can cause harm. A precise understanding of how proteases are involved in aging is needed to interfere with a reduced immune response. With this in mind, our specific protease inhibitors might have the potential as immunomodulators to restore an imbalance of protease activity in aged-related diseases. Furthermore, we are interested in applying immunomodulators, for instance natural food-derived peptides, which might be beneficial to reverse or at least delay immunosenescence. The expected results will also provide an insight in immune cell function by comparing immune cells from aged vs. non-aged donors. Indeed, we can learn general immune functions by evaluating an impaired immune system found in elderly compared to their younger counterparts.
4.2. Tumorigenesis
Cathepsins have a dual role in tumor cell development. In some circumstances, extracellular cathepsins can promote the development of tumors, in contrast to intracellular cathepsins, which are important in apoptosis, can prevent the survival of tumor cells. Cathepsin B and X are upregulated in distinct tumor cells. Moreover, cathepsins and matrix metalloproteinases (MMPs) promote tumor progression and metastasis. Therefore, the regulation and function of cathepsins during the process of tumor development and immune escape are determined in our laboratory. Thereby, we are focusing on antigen processing and presentation in the context of CD8+ T cell activation in a process known as cross presentation/priming. The resulting data allow the development of potent anti-tumor strategies, for instance, the use of specific cathepsin inhibitors.
4.3. Proteolytic regulation of MHC molecules
HIV, for instance, inhibits maturation of major histocompatibility complex class II (MHC II), which is necessarily associated with the Ii processing and cell surface levels of MHC II molecules. Furthermore, the protease involved in proteolytic regulation of MHC I molecules needs to be investigated, particularly towards the process of recycling. We found that there serine protease cathepsin G is responsible for the proteolytic regulation of MHC I molecules, suggesting that there is a correlation between levels of MHC molecules and HIV-mediated protease regulation which is important for HIV-mediated immune evasion.
4.4. CatG and tumorigenesis
Neutrophils release serine proteases, including cathepsin G, proteinase 3, and elastase, at the side of inflammation, which have a broad range of functions: Proteolytic modification of chemokines and cytokines, clearance of internalized pathogens, proteolytic dependent and -independent antimicrobial activity, apoptosis, and tumor progression and metastasis. There are several examples how cathepsins influences the subsequent progression of tumorigenesis by proteolytic activation of pro-MMP9, which is pivotal in TGF-b signaling. TGF-b itself facilitates chemoattraction of tumor cells, accelerates tumor cell growth, and enhances angiogenesis. We are interested in the multiple function of cathepsin G, for instance, the frequency of several cancer types is significantly increased in T1D. It seems most likely that there is a correlation between high levels of proteases, which we detected in dendritic cells (DCs) of type 1 diabetes mellitus (T1D) patients, and the risk of several cancer types in T1D. Thus, our novel cell permeable serine protease inhibitors can be examined and might affect tumorigenesis.
5. Selected publications
Roman Schroeder, Renata Grzywa, Christian Rainer Wirtz, Marcin Sienczyk, and Timo Burster. Application of a novel FAM-conjugated activity-based probe to determine cathepsin G activity intracellularly. 2020. 588, 113488. Analytical Biochemistry.
Lubos Marta, Dębowski Dawid, Barcinska Ewelina, Meid Annika, Inkielewicz-Stepniak Iwona, Burster Timo, and Rolka Krzysztof. Inhibition of human constitutive 20S proteasome and 20S immunoproteasome with novel N-terminally modified peptide aldehydes and their antitumor activity. 2019. e24100. DOI: 10.1002/pep2.24100. Peptide Science.
Adriane Penczek and Timo Burster. Cell surface cathepsin G can be used as an additional marker to distinguish T cell subsets. 2019. Apr; 10 (4):245-249. Biomedical Reports.
Joachim Bischof, Fabian Gärtner, Katja Zeiser, Rebecca Kunz, Corinna Schreiner, Elena Hoffer, Timo Burster, Uwe Knippschild, and Michal Zimecki. Immune cells and immunosenescence. 2019. 65(2):53-63. Folia Biologica. Review.
Pengfei Xu, Chiara Ianes, Fabian Gärtner, Congxing Liu, Johannes Lemke, Timo Burster, Vasiliy Bakulev, Najma Rachidi, Uwe Knippschild, Joachim Bischof. Regulation and functions of the stress-induced CK1 delta: A promising therapeutic target in neurodegenerative diseases and Cancer. 2019. Oct 5;715:144005. doi: 10.1016/j.gene.2019.144005. Gene. Review.
Joachim Bischof, Anna-Laura Kretz, Timo Burster, Doris Henne-Bruns, Uwe Knippschild, and Pengfei Xu. Inhibition of CK1 affects Viability and Survival of Glioblastoma Cells. 2(2). 2018. BJSTR.MS.ID.000735. DOI: 10.26717/BJSTR.2018.02.000735. Biomed J Sci &Tech Res (BJSTR).
Giese, Turiello, Eipper, Molenda, Palesch, Basilico, Benarafa, Marc-Eric Halatsch, Zimecki, Westhoff, Wirtz, and Burster. Exogenous cathepsin G-mediated upregulation of MHC class I molecules in immune and glioblastoma cells. Oncotarget. 2016. Nov. 15;7 (46).
Penczek, Sienczyk, Wirtz, and Burster. Cell surface cathepsin G activity differs between human natural killer subsets. Immunology Letters. 2016. Sep. 24, 80-84.
Mostafa, Pala, Hoegel, Hlavach, Dietrich, Westhoff, Nonnenmacher, Burster, Georgieff, Wirtz, and Schneider. Immune phenotypes predicts survival in patients with glioblastoma multiforme. Journal of Hematology and Oncology. 2016; Sep. 1; 9 (1):77.
Eipper S, Steiner R, Lesner A, Sienczyk M, Palesch D, Halatsch ME, Zaczynska E, Heim C, Hartman M, Zimecki M, Wirtz CR, and Burster T. Lactoferrin is an allosteric enhancer of the proteolytic activity of Cathepsin G. PLoS One. 2016; Mar 17;11.
Palesch D, Wagner J, Annika Meid, Molenda N, Sienczyk M, Muench J, Prokop L, Stevanovic S, Halatsch M, Wirtz CR, Zimecki M, Burster T. Cathepsin G-mediated proteolytic degradation of MHC class I molecules to facilitate immune detection of glioblastoma. Cancer Immunology, Immunotherapy. 2016; Mar 65: 283-291.
Kyeong-Ae K, Ständker L, Zirafi O, Chudziak D, Mohr K, Möpps K, Gierschik P, Vas V, Geiger H, Lamla M, Burster T, Richter R, Daubeu F, Frossard N, Hachet-Haas M, Galzi J, Hancke K, Sandi-Monroy N, Kraft B, Schittek B, Sulyok G, Boenig H, Canales-Mayordomo A, Jiménez-Barbero J, Giménez-Gallego G, Forssmann WG, Kirchhoff F, Münch J. Discovery and characterization of an endogenous CXCR4 antagonist. Cell Reports. 2015; 11 (5): 737-747.
Zou F, Schmon M, Sienczyk M, Grzywa R, Palesch D, Sun Z, Watts C, Schirmbeck R and Burster T. Application of a novel high sensitive activity-based probe for detection of cathepsin G. Anal Biochem. 2012; 421 (2): 667-672.
van Aalst D, Kalbacher H, Palesch P, Spyrantis A, Rosinger S, Boehm BO and Burster T. A proinsulin 73-90-derived protease-resistant altered peptide ligand increases TGF-b1 secretion in PBMC from patients with Type 1 diabetes mellitus. J Leukoc Biol. 2010; 87(5): 943-8.
Burster T, Marin-Esteban V, Boehm BO, Rötzschke O, Falk K, Weber E, Verhelst S, Kalbacher H, and Driessen C: Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions. Biochem. Pharmacology. 2007; 74 (10): 1514-1523.
Burster T, Beck A, Tolosa E, Schnorrer P, Reich M, Krauss M, Kalbacher H, Häring HU, Weisert R, Weber E, Overkleeft H, and Driessen C: Differential processing of autoantigens in lysosomes from human monocyte-derived and peripheral blood dendritic cells. J. Immunol. 2005; 175 (9): 5940-9.
Burster T, Beck A, Tolosa E, Marin-Esteban V, Rötzschke O, Falk K, Lautwein A, Reich M, Brandenburg J, Schwarz G, Wiendl H, Melms A, Lehmann R, Stevanovic S, Kalbacher H, and Driessen C: Cathepsin G, and not the asparagine endoprotease AEP, controls the processing of myelin basic protein in lysosomes from human B lymphocytes. J. Immunol. 2004; 172 (9): 5495-503.
Reviews
Bischof, Westhoff, Wagner, Trentmann, Knippschild, Wirtz, and Burster. Cancer stem cells: Potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells. Tumor Biology. 2017. March;39 (3).
Burster T. Processing and regulation mechanisms within the endocytic compartment of antigen presenting cells: possibility for therapeutic modulation. Current Pharmaceutical Design. 2013; 19 (6): 1029-42.
Burster T, Macmillan H, Hou T, Boehm BO and Mellins ED. Cathepsin G: roles in antigen presentation and byond. Mol Immunol. 2010; 47 (4): 658-665.
Busch R, Rinderknecht C, Roh S, Lee A, Harding JJ, Burster T, Hornell T, and Mellins ED: Achieving stability through editing and chaperoning: Cofactors of antigen presentation and their roles in the regulation of MHC class II peptide binding and expression. Immunol. Rev. 2005; 207: 242-60.
5. Member of the Editorial Board
2017-2019 Editorial Board of Archivum Immunologiae et Therapiae Experimentalis (AITE)
6. Awards
2013 Humboldt Award, Poland