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Septins guide microtubule protrusions induced by actin-depolymerizing toxins like Clostridium difficile transferase (CDT).

  • Nölke T Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79104 Freiburg, Germany;
  • Schwan C Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79104 Freiburg, Germany;
  • Lehmann F Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany; Faculty of Chemistry and Pharmacy, University of Freiburg, 79104 Freiburg, Germany;
  • Østevold K Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany;
  • Pertz O Institute of Cell Biology, University of Bern, 3012 Bern, Switzerland;
  • Aktories K Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, 79104 Freiburg, Germany; Centre for Biological Signalling Studies (BIOSS), University of Freiburg, 79104 Freiburg, Germany; Freiburg Institute of Advanced Studies (FRIAS), University of Freiburg, 79104 Freiburg, Germany klaus.aktories@pharmakol.uni-freiburg.de.
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  • 2016-06-25
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2016
Clostridium difficile
actin
bacterial toxin
microtubules
septins
Animals
Bacterial Toxins
Caco-2 Cells
Clostridium difficile
Dogs
GTP-Binding Protein Regulators
HeLa Cells
Humans
Madin Darby Canine Kidney Cells
Mice, Inbred C57BL
Microtubules
Septins
Transferases
cdc42 GTP-Binding Protein
English Hypervirulent Clostridium difficile strains, which are associated with increased morbidity and mortality, produce the actin-ADP ribosylating toxin Clostridium difficile transferase (CDT). CDT depolymerizes actin, causes formation of microtubule-based protrusions, and increases pathogen adherence. Here, we show that septins (SEPT) are essential for CDT-induced protrusion formation. SEPT2, -6, -7, and -9 accumulate at predetermined protrusion sites and form collar-like structures at the base of protrusions. The septin inhibitor forchlorfenuron or knockdown of septins inhibits protrusion formation. At protrusion sites, septins colocalize with the GTPase Cdc42 (cell division control protein 42) and its effector Borg (binder of Rho GTPases), which act as up-stream regulators of septin polymerization. Precipitation and surface plasmon resonance studies revealed high-affinity binding of septins to the microtubule plus-end tracking protein EB1, thereby guiding incoming microtubules. The data suggest that CDT usurps conserved regulatory principles involved in microtubule-membrane interaction, depending on septins, Cdc42, Borgs, and restructuring of the actin cytoskeleton.
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  • English
Open access status
bronze
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https://sonar.ch/global/documents/278528
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