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Bordetella Adenylate Cyclase Toxin Mobilizes Its β(2) Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps
Bordetella adenylate cyclase toxin (CyaA) binds the α(M)β(2) integrin (CD11b/CD18, Mac-1, or CR3) of myeloid phagocytes and delivers into their cytosol an adenylate cyclase (AC) enzyme that converts ATP into the key signaling molecule cAMP. We show that penetration of the AC domain across cell membr...
Autores principales: | , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869314/ https://www.ncbi.nlm.nih.gov/pubmed/20485565 http://dx.doi.org/10.1371/journal.ppat.1000901 |
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author | Bumba, Ladislav Masin, Jiri Fiser, Radovan Sebo, Peter |
author_facet | Bumba, Ladislav Masin, Jiri Fiser, Radovan Sebo, Peter |
author_sort | Bumba, Ladislav |
collection | PubMed |
description | Bordetella adenylate cyclase toxin (CyaA) binds the α(M)β(2) integrin (CD11b/CD18, Mac-1, or CR3) of myeloid phagocytes and delivers into their cytosol an adenylate cyclase (AC) enzyme that converts ATP into the key signaling molecule cAMP. We show that penetration of the AC domain across cell membrane proceeds in two steps. It starts by membrane insertion of a toxin ‘translocation intermediate’, which can be ‘locked’ in the membrane by the 3D1 antibody blocking AC domain translocation. Insertion of the ‘intermediate’ permeabilizes cells for influx of extracellular calcium ions and thus activates calpain-mediated cleavage of the talin tether. Recruitment of the integrin-CyaA complex into lipid rafts follows and the cholesterol-rich lipid environment promotes translocation of the AC domain across cell membrane. AC translocation into cells was inhibited upon raft disruption by cholesterol depletion, or when CyaA mobilization into rafts was blocked by inhibition of talin processing. Furthermore, CyaA mutants unable to mobilize calcium into cells failed to relocate into lipid rafts, and failed to translocate the AC domain across cell membrane, unless rescued by Ca(2+) influx promoted in trans by ionomycin or another CyaA protein. Hence, by mobilizing calcium ions into phagocytes, the ‘translocation intermediate’ promotes toxin piggybacking on integrin into lipid rafts and enables AC enzyme delivery into host cytosol. |
format | Text |
id | pubmed-2869314 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-28693142010-05-19 Bordetella Adenylate Cyclase Toxin Mobilizes Its β(2) Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps Bumba, Ladislav Masin, Jiri Fiser, Radovan Sebo, Peter PLoS Pathog Research Article Bordetella adenylate cyclase toxin (CyaA) binds the α(M)β(2) integrin (CD11b/CD18, Mac-1, or CR3) of myeloid phagocytes and delivers into their cytosol an adenylate cyclase (AC) enzyme that converts ATP into the key signaling molecule cAMP. We show that penetration of the AC domain across cell membrane proceeds in two steps. It starts by membrane insertion of a toxin ‘translocation intermediate’, which can be ‘locked’ in the membrane by the 3D1 antibody blocking AC domain translocation. Insertion of the ‘intermediate’ permeabilizes cells for influx of extracellular calcium ions and thus activates calpain-mediated cleavage of the talin tether. Recruitment of the integrin-CyaA complex into lipid rafts follows and the cholesterol-rich lipid environment promotes translocation of the AC domain across cell membrane. AC translocation into cells was inhibited upon raft disruption by cholesterol depletion, or when CyaA mobilization into rafts was blocked by inhibition of talin processing. Furthermore, CyaA mutants unable to mobilize calcium into cells failed to relocate into lipid rafts, and failed to translocate the AC domain across cell membrane, unless rescued by Ca(2+) influx promoted in trans by ionomycin or another CyaA protein. Hence, by mobilizing calcium ions into phagocytes, the ‘translocation intermediate’ promotes toxin piggybacking on integrin into lipid rafts and enables AC enzyme delivery into host cytosol. Public Library of Science 2010-05-13 /pmc/articles/PMC2869314/ /pubmed/20485565 http://dx.doi.org/10.1371/journal.ppat.1000901 Text en Bumba et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Bumba, Ladislav Masin, Jiri Fiser, Radovan Sebo, Peter Bordetella Adenylate Cyclase Toxin Mobilizes Its β(2) Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps |
title |
Bordetella Adenylate Cyclase Toxin Mobilizes Its β(2) Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps |
title_full |
Bordetella Adenylate Cyclase Toxin Mobilizes Its β(2) Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps |
title_fullStr |
Bordetella Adenylate Cyclase Toxin Mobilizes Its β(2) Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps |
title_full_unstemmed |
Bordetella Adenylate Cyclase Toxin Mobilizes Its β(2) Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps |
title_short |
Bordetella Adenylate Cyclase Toxin Mobilizes Its β(2) Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps |
title_sort | bordetella adenylate cyclase toxin mobilizes its β(2) integrin receptor into lipid rafts to accomplish translocation across target cell membrane in two steps |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869314/ https://www.ncbi.nlm.nih.gov/pubmed/20485565 http://dx.doi.org/10.1371/journal.ppat.1000901 |
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