Premium
Cytotoxicity of Clostridium difficile toxins A and B requires an active and functional SREBP‐2 pathway
Author(s) -
Papatheodorou Panagiotis,
Song Shuo,
LópezUreña Diana,
Witte Alexander,
Marques Felícia,
Ost Gerhard Stefan,
Schorch Björn,
ChavesOlarte Esteban,
Aktories Klaus
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201801440r
Subject(s) - clostridium difficile , cytotoxicity , microbial toxins , microbiology and biotechnology , medicine , biology , toxin , biochemistry , antibiotics , in vitro
Clostridium difficile is associated with antibiotic‐associated diarrhea and pseudomembranous colitis in humans. Its 2 major toxins, toxins A and B, enter host cells and inactivate GTPases of the Ras homologue/rat sarcoma family by glucosylation. Pore formation of the toxins in the endosomal membrane enables the translocation of their glucosyltransferase domain into the cytosol, and membrane cholesterol is crucial for this process. Here, we asked whether the activity of the sterol regulatory element–binding protein 2 (SREBP‐2) pathway, which regulates the cholesterol content in membranes, affects the susceptibility of target cells toward toxins A and B. We show that the SREBP‐2 pathway is crucial for the intoxication process of toxins A and B by using pharmacological inhibitors (PF‐429242, 25‐hydroxycholesterol) and cells that are specifically deficient in SREBP‐2 pathway signaling. SREBP‐2 pathway inhibition disturbed the cholesterol‐dependent pore formation of toxin B in cellular membranes. Preincubation with the cholesterol‐lowering drug simvastatin protected cells from toxin B intoxication. Inhibition of the SREBP‐2 pathway was without effect when the enzyme portion of toxin B was introduced into target cells via the cell delivery property of anthrax protective antigen. Taken together, these findings allowed us to identify the SREBP‐2 pathway as a suitable target for the development of antitoxin therapeutics against C. difficile toxins A and B.—Papatheodorou, P., Song, S., López‐Ureña, D., Witte, A., Marques, F., Ost, G. S., Schorch, B., Chaves‐Olarte, E., Aktories, K. Cytotoxicity of Clostridium difficile toxins A and B requires an active and functional SREBP‐2 pathway. FASEB J. 33, 4883–4892 (2019). www.fasebj.org