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J. Biol. Chem., Vol. 279, Issue 19, 20200-20210, May 7, 2004

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Granzyme-mediated Cytotoxicity Does Not Involve the Mannose 6-Phosphate Receptors on Target Cells^*

Ralf Dressel, Srikumar M. Raja¶, Stefan Höning||, Tim Seidler**, Christopher J. Froelich¶, Kurt von Figura||, and Eberhard Günther

From the Division of Immunogenetics, University of Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany, the ^¶Evanston Healthcare Research Institute, Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60201, the ^||Division of Biochemistry II, University of Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany, and the ^**Division of Cardiology and Pneumology, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany

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.

Received for publication, December 2, 2003 , and in revised form, February 19, 2004.

^* This work was supported in part by Grant Gu105/16-1 from the Deutsche Forschungsgemeinschaft (to E. G. and R. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: University of Göttingen, Division of Immunogenetics, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany. Tel.: 0049-551-395884; Fax: 0049-551-395852; E-mail: rdresse{at}gwdg.de.

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