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The manner whereby C3 toxins reach the host cell cytoplasm is poorly understood and was addressed in this study by monitoring the fate of fluorescently labeled C3larvinA. Following binding to the macrophage membrane in a discontinuous punctate pattern, the toxin was internalized, traversing the endocytic pathway to reach lysosomes. Strikingly, the lysosomes of C3larvinA\u2010treated cells underwent massive swelling over the course of 1\u20134\u2009h. Lysosomal swelling preceded the extensive rearrangement of the cellular F\u2010actin caused by ADP\u2010ribosylation of cytosolic Rho\u2010GTPases. This suggested that lysosome swelling might be required for the escape of the toxin into the cytoplasm where the GTPases reside. Accordingly, preventing swelling by osmotic manipulation or by arresting macropinocytosis precluded the F\u2010actin rearrangement. Toxin\u2010induced swelling was associated with leakage of sulforhodamine B and dextran from the lysosomes, implying membrane rupture or activation of mechano\u2010sensitive pores, enabling the toxin itself to reach the cytosol. Finally, comparison of the cellular traffic and actin remodeling activities of C3larvinA with that of two related toxins, C3larvin\n                    <jats:sub>trunc<\/jats:sub>\n                    and Plx2A, highlighted the importance of the N\u2010terminal \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    \u2010helix for lysosomal swelling and successful intoxication.\n                  <\/jats:p>","DOI":"10.1111\/mmi.15063","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T23:15:20Z","timestamp":1681168520000},"page":"695-710","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Lysosomal swelling and lysis mediate delivery of C3 toxins to their cytoplasmic targets"],"prefix":"10.1111","volume":"119","author":[{"given":"Madison","family":"Turner","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biology University of Guelph  Guelph Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Plumb","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Peter Gilgan Centre for Research and Learning The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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