Granzyme-mediated cytotoxicity does not involve the mannose 6-phosphate receptors on target cells.
Cytotoxic T lymphocytes (CTL) and natural killer cells secrete granzymes to kill infected or transformed cells. The mannose 6-phosphate receptor (Mpr) 300 on target cells has been reported to function as receptor for secreted granzyme B. Using lymphoblasts and mouse embryonal fibroblast lines from Mpr300 and Mpr46 knockout mice, we show here that both receptors are not essential for CTL-induced apoptosis. Similarly, cells exposed to either monomeric granzyme B or granzyme B-serglycin complexes readily internalize the granzyme and undergo apoptosis in the absence of Mpr300 and Mpr46. Further, no colocalization of granzyme B and Mpr300 could be observed in target cells after internalization. In conclusion, these results strongly argue against an Mpr300- or Mpr46-dependent pathway of granzyme-mediated killing and provide new insight in the internalization of monomeric and complexed granzyme B.
Dressel
Ralf
R
Division of Immunogenetics, University of Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany. rdresse@gwdg.de
Raja
Srikumar M
SM
Höning
Stefan
S
Seidler
Tim
T
Froelich
Christopher J
CJ
von Figura
Kurt
K
Günther
Eberhard
E
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002860:Chromium Radioisotopes; D053938:DNA Fragmentation; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D053804:Granzymes; D015151:Immunoblotting; D008214:Lymphocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011509:Proteoglycans / Q000737:chemistry; D017527:Receptor, IGF Type 2 / Q000737:chemistry* / Q000235:genetics; D012697:Serine Endopeptidases / Q000737:chemistry / Q000502:physiology*; D013936:Thymidine / Q000378:metabolism; D033921:Vesicular Transport Proteins
D002860:Chromium Radioisotopes; C484953:MPR300 protein, rat; D010455:Peptides; D011509:Proteoglycans; D017527:Receptor, IGF Type 2; D033921:Vesicular Transport Proteins; C075430:serglycin; D053804:Granzymes; C509214:Gzmb protein, mouse; C509215:Gzmb protein, rat; D012697:Serine Endopeptidases; D013936:Thymidine