Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence.
Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis by the actions of Rho-glucosylating toxins A and B. Recently identified hypervirulent strains, which are associated with increased morbidity and mortality, additionally produce the actin-ADP-ribosylating toxin C. difficile transferase (CDT). CDT depolymerizes actin, causes formation of microtubule-based protrusions, and increases pathogen adherence. Here we show that CDT-induced protrusions allow vesicle traffic and contain endoplasmic reticulum tubules, connected to microtubules via the calcium sensor Stim1. The toxin reroutes Rab11-positive vesicles containing fibronectin, which is involved in bacterial adherence, from basolateral to the apical membrane sides in a microtubule- and Stim1-dependent manner. The data yield a model of C. difficile adherence regulated by actin depolymerization, microtubule restructuring, subsequent Stim1-dependent Ca(2+) signaling, vesicle rerouting, and secretion of ECM proteins to increase bacterial adherence.
Institute of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany.
Carsten
C
Schwan
Anna S
AS
Kruppke
Thilo
T
Nölke
Lucas
L
Schumacher
Friedrich
F
Koch-Nolte
Mikhail
M
Kudryashev
Henning
H
Stahlberg
Klaus
K
Aktories
D001422:Bacterial Adhesion; D001427:Bacterial Toxins / Q000633:toxicity*; D001692:Biological Transport; D018938:Caco-2 Cells; D020013:Calcium Signaling; D016360:Clostridioides difficile / Q000378:metabolism / Q000472:pathogenicity*; D004721:Endoplasmic Reticulum / Q000187:drug effects; D004768:Enterotoxins / Q000633:toxicity*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000187:drug effects*
D001427:Bacterial Toxins; D004768:Enterotoxins; D005353:Fibronectins; C041348:tcdA protein, Clostridium difficile