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    A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death

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    Author
    Trapani, JA; Sutton, VR; Thia, KYT; Li, YQ; Froelich, CJ; Jans, DA; Sandrin, MS; Browne, KA
    Date
    2003-01-20
    Source Title
    JOURNAL OF CELL BIOLOGY
    Publisher
    ROCKEFELLER UNIV PRESS
    University of Melbourne Author/s
    Trapani, Joseph; LI, YU; Sandrin, Mauro
    Affiliation
    Pathology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Trapani, J. A., Sutton, V. R., Thia, K. Y. T., Li, Y. Q., Froelich, C. J., Jans, D. A., Sandrin, M. S. & Browne, K. A. (2003). A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death. JOURNAL OF CELL BIOLOGY, 160 (2), pp.223-233. https://doi.org/10.1083/jcb.200210150.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/26579
    DOI
    10.1083/jcb.200210150
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172645
    Description

    C1 - Journal Articles Refereed

    Abstract
    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.
    Keywords
    Cell Development (incl. Cell Division and Apoptosis) ; Tumor Immunology ; Cancer and Related Disorders

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