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A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell death
The 280-kD cation-independent mannose-6-phosphate receptor (MPR) has been shown to play a role in endocytic uptake of granzyme B, since target cells overexpressing MPR have an increased sensitivity to granzyme B–mediated apoptosis. On this basis, it has been proposed that cells lacking MPR are poor...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2003
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172645/ https://www.ncbi.nlm.nih.gov/pubmed/12538642 http://dx.doi.org/10.1083/jcb.200210150 |
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author | Trapani, Joseph A. Sutton, Vivien R. Thia, Kevin Y.T. Li, Yu Qin Froelich, Christopher J. Jans, David A. Sandrin, Mauro S. Browne, Kylie A. |
author_facet | Trapani, Joseph A. Sutton, Vivien R. Thia, Kevin Y.T. Li, Yu Qin Froelich, Christopher J. Jans, David A. Sandrin, Mauro S. Browne, Kylie A. |
author_sort | Trapani, Joseph A. |
collection | PubMed |
description | The 280-kD cation-independent mannose-6-phosphate receptor (MPR) has been shown to play a role in endocytic uptake of granzyme B, since target cells overexpressing MPR have an increased sensitivity to granzyme B–mediated apoptosis. On this basis, it has been proposed that cells lacking MPR are poor targets for cytotoxic lymphocytes that mediate allograft rejection or tumor immune surveillance. In the present study, we report that the uptake of granzyme B into target cells is independent of MPR. We used HeLa cells overexpressing a dominant-negative mutated (K44A) form of dynamin and mouse fibroblasts overexpressing or lacking MPR to show that the MPR/clathrin/dynamin pathway is not required for granzyme B uptake. Consistent with this observation, cells lacking the MPR/clathrin pathway remained sensitive to granzyme B. Exposure of K44A-dynamin–overexpressing and wild-type HeLa cells to granzyme B with sublytic perforin resulted in similar apoptosis in the two cell populations, both in short and long term assays. Granzyme B uptake into MPR-overexpressing L cells was more rapid than into MPR-null L cells, but the receptor-deficient cells took up granzyme B through fluid phase micropinocytosis and remained sensitive to it. Contrary to previous findings, we also demonstrated that mouse tumor allografts that lack MPR expression were rejected as rapidly as tumors that overexpress MPR. Entry of granzyme B into target cells and its intracellular trafficking to induce target cell death in the presence of perforin are therefore not critically dependent on MPR or clathrin/dynamin-dependent endocytosis. |
format | Text |
id | pubmed-2172645 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2003 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21726452008-05-01 A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell death Trapani, Joseph A. Sutton, Vivien R. Thia, Kevin Y.T. Li, Yu Qin Froelich, Christopher J. Jans, David A. Sandrin, Mauro S. Browne, Kylie A. J Cell Biol Article The 280-kD cation-independent mannose-6-phosphate receptor (MPR) has been shown to play a role in endocytic uptake of granzyme B, since target cells overexpressing MPR have an increased sensitivity to granzyme B–mediated apoptosis. On this basis, it has been proposed that cells lacking MPR are poor targets for cytotoxic lymphocytes that mediate allograft rejection or tumor immune surveillance. In the present study, we report that the uptake of granzyme B into target cells is independent of MPR. We used HeLa cells overexpressing a dominant-negative mutated (K44A) form of dynamin and mouse fibroblasts overexpressing or lacking MPR to show that the MPR/clathrin/dynamin pathway is not required for granzyme B uptake. Consistent with this observation, cells lacking the MPR/clathrin pathway remained sensitive to granzyme B. Exposure of K44A-dynamin–overexpressing and wild-type HeLa cells to granzyme B with sublytic perforin resulted in similar apoptosis in the two cell populations, both in short and long term assays. Granzyme B uptake into MPR-overexpressing L cells was more rapid than into MPR-null L cells, but the receptor-deficient cells took up granzyme B through fluid phase micropinocytosis and remained sensitive to it. Contrary to previous findings, we also demonstrated that mouse tumor allografts that lack MPR expression were rejected as rapidly as tumors that overexpress MPR. Entry of granzyme B into target cells and its intracellular trafficking to induce target cell death in the presence of perforin are therefore not critically dependent on MPR or clathrin/dynamin-dependent endocytosis. The Rockefeller University Press 2003-01-20 /pmc/articles/PMC2172645/ /pubmed/12538642 http://dx.doi.org/10.1083/jcb.200210150 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Trapani, Joseph A. Sutton, Vivien R. Thia, Kevin Y.T. Li, Yu Qin Froelich, Christopher J. Jans, David A. Sandrin, Mauro S. Browne, Kylie A. A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell death |
title | A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell death |
title_full | A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell death |
title_fullStr | A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell death |
title_full_unstemmed | A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell death |
title_short | A clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme B–induced cell death |
title_sort | clathrin/dynamin- and mannose-6-phosphate receptor–independent pathway for granzyme b–induced cell death |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172645/ https://www.ncbi.nlm.nih.gov/pubmed/12538642 http://dx.doi.org/10.1083/jcb.200210150 |
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