Cluster of Excellence –
University of Freiburg

Prof. Dr. Klaus Aktories

Prof. Dr. Klaus Aktories

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg

+49 761 203 5301

We study signaling of eukaryotic cells involved in host-pathogen interactions, which are affected by bacterial protein toxins. These signal pathways are frequently controlled by diverse types of GTP-binding proteins and cytoskeletal proteins like actin and microtubules. The GTP-binding proteins and cytoskeletal proteins are covalently modified by the bacterial toxins. Because the toxins are highly specific and extremely potent, they are employed as cell biological tools to decipher signal pathways in which their eukaryotic targets are involved.

Focus is on various clostridial glucosylating toxins (e.g., Clostridium difficile toxins A and B, C. sordellii lethal toxin and C. novyi alpha-toxin), which are pathogenic factors involved in pseudomembranous colitis, antibiotics-associated diarrhea, toxic shock syndrome and gas gangrene, respectively. All these toxins inactivate Rho/Ras GTPases by mono-O-glucosylation or O-GlcNAcylation. Other toxins from Photorhabdus asymbiotica and Yersinia ruckeri inhibit Rho GTPases by tyrosine-glycosylation (1, 2, 3). Rho GTPases are not only inhibited but also activated by toxins: Examples are the cytotoxic necrotizing factors (CNFs) from E. coli (1) and Photorhabdus luminescens Tc toxin (3) , which activate Rho GTPases by deamidation and ADP-ribosylation, respectively. Another group of toxins from Legionella pneumophila glucosylates the GTP-binding protein elongation factor 1A of target cells thereby inhibiting protein synthesis (4). Heterotrimeric G proteins from the Gq, Gi and G12/13 family are targets of Pasteurella multocida toxin (PMT) (1). This toxin deamidates and constitutively activates alpha-subunits of heterotrimeric G proteins thereby affecting Rho- and Jak/Stat-signaling, mitogenic and anti-apoptotic pathways. Another large group of toxins, which are studied in our laboratory, ADP-ribosylates actin to inhibit (binary actin-ADP-ribosylating toxins (5)) or induce (P. luminescens TccC5 (4)) actin polymerization.

The studies aim to elucidate the mode of actions of toxins, toxin up-take and processing as well as the functional consequences of the action on signaling pathways of eukaryotic target cells.

References

  1. Aktories K. (2011) Nat. Rev. Microbiol., 9, 487-498.
  2. Schorch, B., Song, S., van Diemen, F. R., Bock, H. H., May, P., Herz, J., Brummelkamp, T.R., Papatheodorou, P., and Aktories, K. (2014). Proc. Natl. Acad. Sci. USA, 111, 6431-6436.
  3. Jank, T., Bogdanovic, X., Wirth, C., Haaf, E., Spoerner, M., Bohmer, K. E., Steinemann, M., Orth, J. H., Kalbitzer, H.R., Warscheid, B., Hunte, C., and Aktories, K. (2013) Nat. Struct. Mol. Biol., 20, 1273-1280.
  4. Lang, A. E., Schmidt, G., Schlosser, A., Hey, T. D., Larrinua, I. M., Sheets, J. J., Mannherz, H.-G., and Aktories, K. (2010) Science 327, 1139-1142
  5. Schwan, C., Kruppke, A. S., Nolke, T., Schumacher, L., Koch-Nolte, F., Kudryashev, M., Stahlberg, H., and Aktories, K. (2014) Proc. Natl. Acad. Sci. USA, 111, 2313-2318

10 selected publications:

  • Tyrosine glycosylation of Rho by Yersinia toxin impairs blastomere cell behaviour in zebrafish embryos.
    Jank T, Eckerle S, Steinemann M, Trillhaase C, Schimpl M, Wiese S, van Aalten DM, Driever W, and Aktories K (2015)
    Nat Commun, 6, 7807
  • LRP1 is a receptor for Clostridium perfringens TpeL toxin indicating a two-receptor model of clostridial glycosylating toxins.
    Schorch B, Song S, van Diemen FR, Bock HH, May P, Herz J, Brummelkamp TR, Papatheodorou P, and Aktories K (2014)
    Proc Natl Acad Sci U S A, 111, 6431-6436
  • Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence.
    Schwan C, Kruppke AS, Nolke T, Schumacher L, Koch-Nolte F, Kudryashev M, Stahlberg H, and Aktories K (2014)
    Proc Natl Acad Sci U S A, 111, 2313-2318
  • A bacterial toxin catalyzing tyrosine glycosylation of Rho and deamidation of Gq and Gi proteins.
    Jank T, Bogdanovic X, Wirth C, Haaf E, Spoerner M, Bohmer KE, Steinemann M, Orth JH, Kalbitzer HR, Warscheid B, Hunte C, and Aktories K (2013)
    Nat Struct Mol Biol, 20, 1273-1280
  • A syringe-like injection mechanism in Photorhabdus luminescens toxins.
    Gatsogiannis C, Lang AE, Meusch D, Pfaumann V, Hofnagel O, Benz R, Aktories K, and Raunser S (2013)
    Nature, 495, 520-523
  • Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT).
    Papatheodorou P, Carette JE, Bell GW, Schwan C, Guttenberg G, Brummelkamp TR, and Aktories K (2011)
    Proc Natl Acad Sci U S A, 108, 16422-16427
  • Photorhabdus luminescens toxins ADP-ribosylate actin and RhoA to force actin clustering.
    Lang AE, Schmidt G, Schlosser A, Hey TD, Larrinua IM, Sheets JJ, Mannherz HG, Aktories K (2010)
    Science 327,1139-1142
  • Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria.
    Schwan C, Stecher B, Tzivelekidis T, van Ham M, Rohde M, Hardt WD, Wehland J, Aktories K (2009)
    Plos Pathogens, doi:10.1371/journal.ppat.1000626
  • Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation.
    Orth JH, Preuss I, Fester I, Schlosser A, Wilson BA, Aktories K (2009).
    Proc. Natl. Acad. Sci. USA 17,7179-7184
  • Human alpha-defensins inhibit Clostridium difficile toxin B.
    Giesemann T, Guttenberg G, Aktories K (2008)
    Gastroenterology 134, 2049-2058