Selective Degradation of Cytosolic Proteins by Direct Transport Into Lysosomes

  • Dice J
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Abstract

Lysosomes are able to internalize cellular proteins in a variety of ways. One pathway is selective for cytosolic proteins containing peptide sequences biochemically related to Lys-Phe-Glu-Arg-Gln (KFERQ). This pathway is activated in confluent monolay-ers of cultured cells in response to deprivation of serum growth factors and applies to approximately 30% of cytosolic proteins. Intact animals also activate this pro-teolytic pathway in tissues such as liver, kidney, and heart in response to fasting. We have reconstituted this lysosomal degradation pathway in vitro using highly purified lysosomes. Uptake and degradation of substrate proteins are stimulated by ATP and a member of the heat-shock 70-kDa protein family, the 73-kDa constitutive heat-shock protein (hsc73). This pathway is selective since ribonuclease A and ribonuclease S-peptide are good substrates, but ribonuclease S-protein is not. Fur-thermore, the uptake mechanism is saturable, and at 4 °C substrate proteins bind specifically to a protein component of lysosomal membranes, presumably a receptor or polypeptide transporter. A portion of cellular hsc73 is associated with lysosomes both on the cytoplasmic face of the lysosomal membrane and within the lysosomal lumen. Hsc73 within the lumen is required for polypeptide import into the organelle. These results indicate that the lysosomal polypeptide import process is strikingly similar to those for import of proteins for residence in other organelles. © 1995 Elsevier Inc.

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Authors

  • J. Fred Dice

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