A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death
AuthorTrapani, JA; Sutton, VR; Thia, KYT; Li, YQ; Froelich, CJ; Jans, DA; Sandrin, MS; Browne, KA
Source TitleJOURNAL OF CELL BIOLOGY
PublisherROCKEFELLER UNIV PRESS
Document TypeJournal Article
CitationsTrapani, JA; Sutton, VR; Thia, KYT; Li, YQ; Froelich, CJ; Jans, DA; Sandrin, MS; Browne, KA, A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death, JOURNAL OF CELL BIOLOGY, 2003, 160 (2), pp. 223 - 233
Access StatusAccess this item via the Open Access location
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172645
C1 - Journal Articles Refereed
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.
KeywordsCell Development (incl. Cell Division and Apoptosis) ; Tumor Immunology ; Cancer and Related Disorders
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