Lysosomal swelling and lysis mediate delivery of C3 toxins to their cytoplasmic targets.
| Autor: | Turner M; Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada., Plumb J; Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada., Merrill AR; Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada., Grinstein S; Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.; Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada., Westman J; Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada. |
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| Jazyk: | angličtina |
| Zdroj: | Molecular microbiology [Mol Microbiol] 2023 Jun; Vol. 119 (6), pp. 695-710. Date of Electronic Publication: 2023 Apr 10. |
| DOI: | 10.1111/mmi.15063 |
| Abstrakt: | Unlike other cholera-like toxins that contain separate binding/translocation and catalytic subunits, C3-like mono-ADP-ribosyltransferases consist of a single subunit that serves both functions. 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-treated cells underwent massive swelling over the course of 1-4 h. Lysosomal swelling preceded the extensive rearrangement of the cellular F-actin caused by ADP-ribosylation of cytosolic Rho-GTPases. 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-actin rearrangement. Toxin-induced swelling was associated with leakage of sulforhodamine B and dextran from the lysosomes, implying membrane rupture or activation of mechano-sensitive 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 (© 2023 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.) |
| Databáze: | MEDLINE |
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