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First published online 20 November 2002
doi: 10.1242/jcs.00214

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Secretory ribonucleases are internalized by a dynamin-independent endocytic pathway

Marcia C. Haigis^1,* and Ronald T. Raines^1,2,

¹ Department of Biochemistry, University of Wisconsin—Madison, Madison, Wisconsin 53706, USA
² Department of Chemistry, University of Wisconsin—Madison, Madison, Wisconsin 53706, USA
^* Current address: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA

Author for correspondence (e-mail: raines{at}biochem.wisc.edu)

Accepted 10 October 2002

Cytosolic internalization is a requirement for the toxicity of secretory ribonucleases. Here, we investigate the mechanism of internalization of Onconase® (ONC), a toxic protein, and ribonuclease A (RNase A), a nontoxic homolog. Microscopy studies indicate that both ribonucleases readily bind to the cell surface and are internalized via acidic vesicles. Blocking dynamin-dependent endocytosis prevents transferrin internalization but does not hinder RNase A internalization. ONC and G88R RNase A, which is a toxic variant, demonstrate enhanced cytotoxicity in the absence of clathrin- and dynamin-mediated endocytosis. The cytosolic entry of ribonucleases does not require an acidic environment or transport to the ER and probably occurs from endosomes. Thus, common proteins — secretory ribonucleases — enter the cytosol by a pathway that is distinct from that of other known toxins.

Key words: Dynamin, Endocytosis, Endosome, Ribonuclease, Toxin

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