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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\u2013binding protein 2 (SREBP\u20102) pathway, which regulates the cholesterol content in membranes, affects the susceptibility of target cells toward toxins A and B. We show that the SREBP\u20102 pathway is crucial for the intoxication process of toxins A and B by using pharmacological inhibitors (PF\u2010429242, 25\u2010hydroxycholesterol) and cells that are specifically deficient in SREBP\u20102 pathway signaling. SREBP\u20102 pathway inhibition disturbed the cholesterol\u2010dependent pore formation of toxin B in cellular membranes. Preincubation with the cholesterol\u2010lowering drug simvastatin protected cells from toxin B intoxication. Inhibition of the SREBP\u20102 pathway was without effect when the enzyme portion of toxin B was introduced into target cells\n                    <jats:italic>via<\/jats:italic>\n                    the cell delivery property of anthrax protective antigen. Taken together, these findings allowed us to identify the SREBP\u20102 pathway as a suitable target for the development of antitoxin therapeutics against C.\n                    <jats:italic>difficile<\/jats:italic>\n                    toxins A and B.\u2014Papatheodorou, P., Song, S., L\u00f3pez\u2010Ure\u00f1a, D., Witte, A., Marques, F., Ost, G. S., Schorch, B., Chaves\u2010Olarte, E., Aktories, K. Cytotoxicity of\n                    <jats:italic>Clostridium difficile<\/jats:italic>\n                    toxins A and B requires an active and functional SREBP\u20102 pathway. FASEB J. 33, 4883\u20134892 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201801440r","type":"journal-article","created":{"date-parts":[[2018,12,28]],"date-time":"2018-12-28T13:13:20Z","timestamp":1546002800000},"page":"4883-4892","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Cytotoxicity of\n                    <i>Clostridium difficile<\/i>\n                    toxins A and B requires an active and functional SREBP\u20102 pathway"],"prefix":"10.1096","volume":"33","author":[{"given":"Panagiotis","family":"Papatheodorou","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Experimentelle und Klinische Pharmakologie und Toxikologie Medizinische Fakult\u00e4t Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuo","family":"Song","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Experimentelle und Klinische Pharmakologie und Toxikologie Medizinische Fakult\u00e4t Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"L\u00f3pez\u2010Ure\u00f1a","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Enfermedades Tropicales Facultad de Microbiolog\u00eda Universidad de Costa Rica  San Jos\u00e9 Costa Rica"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Witte","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Experimentelle und Klinische Pharmakologie und Toxikologie Medizinische Fakult\u00e4t Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fel\u00edcia","family":"Marques","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Experimentelle und Klinische Pharmakologie und Toxikologie Medizinische Fakult\u00e4t Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerhard Stefan","family":"Ost","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Experimentelle und Klinische Pharmakologie und Toxikologie Medizinische Fakult\u00e4t Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bj\u00f6rn","family":"Schorch","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Experimentelle und Klinische Pharmakologie und Toxikologie Medizinische Fakult\u00e4t Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esteban","family":"Chaves\u2010Olarte","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Enfermedades Tropicales Facultad de Microbiolog\u00eda Universidad de Costa Rica  San Jos\u00e9 Costa Rica"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Aktories","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Experimentelle und Klinische Pharmakologie und Toxikologie Medizinische Fakult\u00e4t Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,12,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.18.2.247-263.2005"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0707500"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-090816-093458"},{"key":"e_1_2_8_5_1","first-page":"79","article-title":"Receptors and binding structures for Clostridium difficile toxins a and B","volume":"406","author":"Gerhard R.","year":"2017","journal-title":"Curr. 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