Professor Matthias Trost
Professor of Proteomics
- Email: firstname.lastname@example.org
- Telephone: +44 (0) 191 208 7009
- Personal Website: http://www.trostlab.org
- Address: Institute for Cell and Molecular Biosciences Faculty of Medical Sciences
Newcastle upon Tyne
since 2016 Professor of Proteomics, Newcastle University, Newcastle-upon-Tyne
2010-2017 Programme Leader (PI) and Head of Proteomics at the MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Scotland
2006-2010 Post-Doctoral Position, later Research Associate with Pierre Thibault, Institute in Research in Immunology and Cancer (IRIC), Montréal, Canada
2005-2006 Post-Doctoral Position with Michel Desjardins, Université de Montréal, Canada
2001-2004 PhD in Cellular Microbiology & Proteomics (Supervisor: Lothar Jänsch & Jürgen Wehland, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany): “Functional genome analysis of secretory proteins and the Host-Pathogen-Interactions of the human pathogen Listeria monocytogenes”
2001 Diploma in Chemistry, Thesis in the group of Peter Gräber (Biophysical Chemistry, University of Freiburg): ‘The H+-ATP-Synthase of Escherichia coli’.
1995-1996 BSc (Hons.) in Chemistry at the University of Manchester in Science and Technology (UMIST) (now: University of Manchester), Third Year Project: Analysis of peptide mixtures by MALDI TOF MS (Supervisor: Simon J. Gaskell, Michael-Barber-Centre for Mass Spectrometry)
1993-2000 Study of Chemistry at the University of Freiburg, Germany
Mass spectrometry (MS)-based proteomics has developed at an astonishing pace over the last 20 years. This progress is largely due to the development of new powerful mass spectrometers. However, sample preparation, chromatography as well as data analysis and visualisation have not kept up with this development and new tools in these areas are required in order to utilise the potential of these mass spectrometers. A particular problem is that many proteomes display a very wide range of protein concentrations between high-abundance and low-abundance proteins sometimes in the order of 108 or even higher. In human serum for example, 10 proteins make up 90% of the protein content. Unfortunately, most mass spectrometers are physically limited to a linear dynamic range of ~103. To overcome this technically challenging problem, samples need to be fractionated by an additional chromatographic step.
My lab has in recent years focussed on developing and establishing proteomics techniques that allow us to answer important biological questions. Our published work was directed towards two aims: 1. Increasing the number of proteins identified in proteomics experiments whilst keeping or reducing the sample amount and instrument time. 2. Developing a MALDI TOF mass spectrometry-based assay to characterise chain specificity and activity of deubiquitylases (DUBs).
Understanding Phagosome Biology
The biological focus of my lab is on macrophage innate immune responses and phagosome biology. Macrophages are highly diverse and plastic immune cells that can polarise in response to environmental cues into many different phenotypes. The two best characterised functional phenotypes are the inflammatory M1 phenotype “classically” activated through Toll-like receptor (TLR) agonists and interferons, and the anti-inflammatory M2 phenotype “alternatively” activated through interleukins-4 or 13 which are secreted during wound-healing and parasite infections. However, given the fact that macrophages possess regulatory receptors for a bewildering array of growth factors, cytokines, chemokines, prostanoids, etc., this binary divide is intrinsically unlikely. A more sustainable view sees macrophage polarization more in the nature of a much broader multi-dimensional model.2 Moreover, there is a huge diversity of tissue-resident macrophages with important and diverse functions in virtually every human organ, for example microglia in the brain, Kupffer cells in the liver and the three different described subsets of macrophages in the lymph node. Because of their importance and this diversity, it is not surprising that dysregulated macrophage polarization is frequently associated with disease.
Macrophages are important phagocytes that clear apoptotic cells and cellular debris during development and tissue homeostasis as well as pathogenic microbes during infection. Phagocytosis can be defined as the uptake of large particles (~0.5-10 μm) by cells. It is an important cellular mechanism for all eukaryotes and highly conserved in evolution: while lower eukaryotes phagocytose for food, multicellular organisms have developed specialized phagocytic cells such as macrophages as a key part of the innate immune response. Phagocytosis is induced through binding of particles as diverse as inert beads, microbes or apoptotic cells to a variety of cell surface receptors. After internalization, newly formed phagosomes engage in a maturation process that involves fusion with endosomal populations and ultimately with lysosomes, leading to the formation of phagolysosomes where the foreign matter within is degraded. Microbe degradation in the phagosome produces antigens, which are presented at the cell surface to activate specific lymphocytes and elicit appropriate immune responses, linking innate to adaptive immunity.
Phagosomes are highly complex organelles that are in constant change due to fission and fusion with other organelles. The use of latex or polystyrene beads as inert baits for phagocytosis enables the purification of highly enriched phagosomes. Proteomics analyses on these pure phagosome fractions revealed contributions of the endoplasmic reticulum (ER) to the phagosomal membrane and its consequences on MHC class I peptide cross-presentation. In my post-doc, I analysed latex bead phagosomes of resting and interferon-γ (IFN-γ) activated macrophages, showing – among other things - that antigen presentation is preferred over fast microbe degradation in activated macrophages.
Our understanding of phagosome biology is of great importance as several pathogens including Leishmania, Brucella and Legionella species, and, most prominently, Mycobacterium tuberculosis are able to subvert phagosome maturation allowing them to survive as intracellular pathogens. In particular tuberculosis has been identified as a major global health threat by the World Health Organisation (WHO)16 with 9.4 million incident cases, 14 million prevalent cases and 1.68 million deaths in 2009 alone, highlighting the importance of our understanding of phagosome function during infection.
Moreover, phagosomal, endosomal and autophagosomal delivery to the lysosome is controlled by the same vesicular trafficking complexes. But while phagosomes can be isolated to a high purity, endosomes and autophagosomes cannot. This offers a unique chance to characterise conserved principles in these pathways employing proteomics, cell biological and biochemical tools. It will give insights into broader biological contexts such as many neurodegenerative diseases that are caused by mutations in proteins important for lysosomal delivery.
The key questions we want to understand are how proinflammatory signals are transduced from the phagosome and how proinflammatory activation regulates vesicle trafficking of the phagosome. We focus our studies on characterising the roles of ubiquitylation and phosphorylation in these pathways and to understand the molecular details of immune responses and how the phagolysosomal destruction of phagocytosed prey is orchestrated.
TeachingCurrently no teaching.
- Selvan N, Williamson R, Mariappa D, Campbell DG, Gourlay R, Ferenbach AT, Aristotelous T, Hopkins-Navratilova I, Trost M, Van Aalten DMF. A mutant O-GlcNAcase enriches Drosophila developmental regulators. Nature Chemical Biology 2017, 13(8), 882-887.
- Peltier J, Härtlova A, Trost M. Assessing the Phagosome Proteome by Quantitative Mass Spectrometry. In: Roberto Botelho, ed. Phagocytosis and Phagosomes: Methods and Protocols. New York: Springer, 2017, pp.249-263.
- Heap RE, Hope AG, Pearson L-A, Reyskens KMSE, McElroy SP, Hastie CJ, Porter DW, Arthur JSC, Gray DW, Trost M. Identifying Inhibitors of Inflammation: A Novel High-Throughput MALDI-TOF Screening Assay for Salt-Inducible Kinases (SIKs). SLAS Discovery 2017, 22(10), 1193-1202.
- Härtlova A, Peltier J, Bilkei-Gorzo O, Trost M. Isolation and Western Blotting of Latex-Bead Phagosomes to Track Phagosome Maturation. In: Roberto Botelho, ed. Phagocytosis and Phagosomes: Methods and Protocols. New York: Springer, 2017, pp.241-248.
- Magiera K, Tomala M, Kubica K, De Cesare V, Trost M, Zieba BJ, Kachamakova-Trojanowska N, Les M, Dubin G, Holak TA, Skalniak L. Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G0/G1 Arrest by Inhibiting Deubiquitinase USP2a. Cell Chemical Biology 2017, 24(4), 458-470.e18.
- Heap RE, Gant MS, Lamoliatte F, Peltier J, Trost M. Mass spectrometry techniques for studying the ubiquitin system. Biochemical Society Transactions 2017, 45(5), 1137-1148.
- Pauwels AM, Trost M, Beyaert R, Hoffmann E. Patterns, Receptors, and Signals: Regulation of Phagosome Maturation. Trends in Immunology 2017, (ePub ahead of Print).
- Kategaya L, Di Lello P, Rouge L, Pastor R, Clark KR, Drummond J, Kleinheinz T, Lin E, Upton J-P, Prakash S, Heideker J, McCleland M, Ritorto MS, Alessi DR, Trost M, Bainbridge TW, Kwok MCM, Ma TP, Stiffler Z, Brasher B, Tang Y, Jaishankar P, Hearn BR, Renslo AR, Arkin MR, Cohen F, Yu K, Peale F, Gnad F, Chang MT, Klijn C, Blackwood E, Martin SE, Forrest WF, Ernst JA, Ndubaku C, Wang X, Beresini MH, Tsui V, Schwerdtfeger C, Blake RA, Murray J, Maurer T, Wertz IE. USP7 small-molecule inhibitors interfere with ubiquitin binding. Nature 2017, 550(7677), 534-538.
- McGuire VA, Ruiz-Zorrilla Diez T, Emmerich CH, Strickson S, Ritorto MS, Weiss A, Houslay KF, Knebel A, Meakin P, Ashford M, Trost M, Arthur JSC. Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Scientific Reports 2016, 6, 31159.
- Naujoks J, Tabeling C, Dill BD, Hoffmann C, Brown AS, Kunze M, Kempa S, Peter A, Mollenkopf HJ, Dorhoi A, Kershaw O, Gruber A, Sander LE, Witzenrath M, Herold S, Nerlich A, Hocke AC, van Driel I, Suttorp N, Bedoui S, Hilbi H, Trost M, Opitz B. IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid. PLOS Pathogens 2016, 12(2), e1005408.
- Gandin V, Masvidal L, Gyenis L, McLaughlan S, Tenkerian C, Koromilas A, Stambolic V, Larose L, Asano K, Trost M, Litchfield D, Larsson O, Topisirovic I. mTORC1 and CK2 coordinate ternary and eIF4F complex assembly. Nature Communications 2016, 7, 11127.
- Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M, Wachter S, Lorentzen E, Duddy G, Wilson S, Baptista M, Fiske B, Fell MJ, Morrow JA, Reith AD, Alessi DR, Mann M. Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 2016, 5, e12813.
- Huguenin-Dezot N, De Cesare V, Peltier J, Knebel A, Kristaryianto YA, Kulathu Y, Trost M, Chin JW. Synthesis of Isomeric Phosphoubiquitin Chains Reveals that Phosphorylation Controls Deubiquitinase Activity and Specificity. Cell Reports 2016, 16(4), 1180-1193.
- Hjerpe R, Bett J, Keuss MJ, Solovyova A, McWilliams TG, Johnson C, Sahu I, Varghese J, Wood N, Wightman M, Osbourne G, Bates GP, Glickman MH, Trost M, Knebel A, Marchesi F, Kurz T. UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome. Cell 2016, 166(4), 935–949.
- Cianfanelli FR, Alcoforado Diniz J, Guo M, de Cesare V, Trost M, Coulthurst D. VgrG and PAAR proteins define distinct versions of a functional Type VI secretion system. PLoS Pathogens 2016, 12(6), e1005735.
- Kazlauskaite A, Martínez Torres RJ, Wilkie S, Kumar A, Peltier J, Gonzalez A, Johnson C, Zhang J, Hope AG, Peggie M, Trost M, van Aalten DMF, Alessi DR, Prescott AR, Knebel A, Walden H, Muqit MMK. Binding to serine 65‐phosphorylated ubiquitin primes Parkin for optimal PINK1‐dependent phosphorylation and activation. EMBO Reports 2015, 16(8), 939-954.
- Guo M, Hartlova A, Dill BD, Prescott AR, Gierlinski M, Trost M. High-resolution quantitative proteome analysis reveals substantial differences between phagosomes of RAW 264.7 and bone marrow-derived macrophages. Proteomics 2015, 15(18), 3169–3174.
- Lai YC, Kondapalli C, Lehneck R, Procter J, Dill BD, Woodroof HI, Gourlay R, Peggie M, Macartney TJ, Corti O, Corvol J-C, Campbell DG, Itzen A, Trost M, Muqit MMK. Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1. EMBO Journal 2015, 34(22), 2840-2861.
- Dill BD, Gierlinski M, Hartlova A, Gonzalez Arandilla A, Guo M, Clarke RG, Trost M. Quantitative proteome analysis of temporally-resolved phagosomes following uptake via key phagocytic receptors. Molecular and Cellular Proteomics 2015, 14, 1334-1349.
- Bett JS, Ritorto MS, Ewan R, Jaffray E, Virdee S, Chin J, Knebel A, Kurz T, Trost M, Tatham MH, Hay RT. Ubiquitin C-terminal hydrolases cleave isopeptide- and peptide-linked ubiquitin from structured proteins but do not edit ubiquitin homopolymers. Biochemical Journal 2015, 466(3), 489-498.
- Gawden-Bone C, West MA, Edgar AJ, Dill BD, Trost M, Morrison VL, Prescott A, Fagerholm SC, Watts C. A crucial role for β2 integrins in podosome formation, dynamics and Toll-like-receptor-signaled disassembly in dendritic cells. Journal of Cell Science 2014, 127(19), 4213-4224.
- Hamilton JJ, Marlow VL, Buchanan G, Guo M, Owen R, de Assis Alcoforado Costa M, Trost M, Coulthurst SJ, Palmer T, Stanley-Wall NR, Sargent F. A holin and an endopeptidase are essential for chitinolytic protein secretion in Serratia marcescens. Journal of Cell Biology 2014, 207(5), 615-626.
- Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Hofmann K, Alessi DR, Knebel A, Trost M, Muqit MMK. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Serine65. Biochemical Journal 2014, 460(1), 127-141.
- Navarro MN, Feijoo-Carnero C, Gonzalez Arandilla A, Trost M, Cantrell DA. Protein kinase D2 is a digital amplifier of T cell receptor–stimulated diacylglycerol signaling in naïve CD8+ T cells. Science Signaling 2014, 7(348), ra99.
- Tape JC, Worboys JD, Sinclair J, Gourlay R, Vogt J, Trost M, Lauffenburger DA, Lamont DJ, Jorgensen C. Reproducible Automated Phosphopeptide Enrichment using Magnetic TiO2 and Ti-IMAC. Analytical Chemistry 2014, 86(20), 10296–10302.
- Ritorto MS, Ewan R, PerezOliva A, Knebel A, Buhrlage SJ, Wightman M, Wood NT, Gray NS, Morrice NA, Alessi DR, Trost M. Screening of DUB activity and specificity by MALDI-TOF mass spectrometry. Nature Communications 2014, 5, 4763.
- Edgar AJ, Trost M, Watts C, Zaru R. A combination of SILAC and nucleotide acyl phosphate labelling reveals unexpected targets of the Rsk inhibitor BI-D1870. Biosci Rep 2013.
- Ritorto MS, Cook K, Tyagi K, Pedrioli P, Trost M. Hydrophilic Strong-Anion Exchange chromato-graphy for highly orthogonal peptide separation of complex proteomes. J Proteome Res 2013.
- Ritorto MS, Trost M, Cook K. Hydrophilic Strong-Anion Exchange chromatography for proteomics: what’s the future outlook?. Bioanalysis 2013.
- Fritsch MJ, Trunk K, AlcoforadoDiniz J, Guo M, Trost M, Coulthurst SJ. Proteomic identification of novel secreted anti-bacterial toxins of the Serratia marcescens type VI secretion system. Mol Cell Proteomics 2013.
- Trost M, Sauvageau M, Herault O, Deleris P, Pomies C, Chagraoui J, Mayotte N, Meloche S, Sauvageau G, Thibault P. Post-translational regulation of self-renewal capacity: insights from proteome and phosphoproteome analyses of stem cell leukemia. Blood 2012.
- Campbell-Valois FX, Trost M, Chemali M, Dill BD, Laplante A, Duclos S, Sadeghi S, Rondeau C, Morrow IC, Bell C, Gagnon E, Hatsuzawa K, Thibault P, Desjardins M. Quantitative proteomics reveals that only a subset of the endoplasmic reticulum contributes to the phagosome. Mol Cell Proteomics 2012.
- Deleris P, Trost M, Topisirovic I, Tanguay PL, Borden KL, Thibault P, Meloche S. Activation loop phosphorylation of ERK3/ERK4 by group I PAKs defines a novel PAK-ERK3/4-MK5 signaling pathway. J Biol Chem 2011.
- Trunk K, Benkert B, Quack N, Munch R, Scheer M, Garbe J, Jansch L, Trost M, Wehland J, Buer J, Jahn M, Schobert M, Jahn D. Anaerobic adaptation in Pseudomonas aeruginosa: definition of the Anr and Dnr regulons. Environ Microbiol 2010.
- Boulais J, Trost M, Landry CR, Dieckmann R, Levy ED, Soldati T, Michnick SW, Thibault P, Desjardins M. Molecular characterization of the evolution of phagosomes. Mol Syst Biol 2010.
- Trost M, Bridon G, Desjardins M, Thibault P. Subcellular phosphoproteomics. Mass Spectrom Rev 2010.
- Trost M, English L, Lemieux S, Courcelles M, Desjardins M, Thibault P. . Immunity 2009.
- Topisirovic I, Siddiqui N, Lapointe VL, Trost M, Thibault P, Piñol-Roma S, Borden KLB. Molecular Dissection of the mRNA export competent eIF4E RNP. EMBO Journal 2009.
- Marcantonio M, Trost M, Courcelles M, Desjardins M, Thibault P. Combined enzymatic and data mining approaches for comprehensive phosphoproteome analyses. Mol Cell Proteomics 2008.
- Layer G, Pierik AJ, Trost M, Rigby SE, Leech HK, Grage K, Breckau D, Astner I, Jansch L, Heathcote P, Warren MJ, Heinz DW, Jahn D. The substrate radical of Escherichia coli oxygen-independent coproporphyrinogen III oxidase HemN. J Biol Chem 2006.
- Trost M, Wehmhöner D, Kärst U, Dieterich G, Wehland J, Jänsch L. Comparative proteome analysis of secretory proteins from pathogenic and nonpathogenic Listeria species. Proteomics 2005.
- Jacobsen I, Hennig-Pauka I, Baltes N, Trost M, Gerlach GF. Enzymes involved in anaerobic respiration appear to play a role in Actinobacillus pleuropneumoniae virulence. Infect Immun 2005.
- Borsch M, Diez M, Zimmermann B, Trost M, Steigmiller S, Graber P. Stepwise rotation of the γ-subunit of EFoF1-ATP synthase during ATP synthesis: a single-molecule FRET approach. Proc. SPIE 2003.
- Bierne H, Mazmanian SK, Trost M, Pucciarelli MG, Liu G, Dehoux P, Jansch L, Garcia-delPortillo F, Schneewind O, Cossart P. Inactivation of the srtA gene in Listeria monocytogenes inhibits anchoring of surface proteins and affects virulence. Mol. Microbiol 2002.