Journal of Biological Chemistry
Volume 272, Issue 9, 28 February 1997, Pages 5606-5615
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Cell Biology and Metabolism
A Population of Rat Liver Lysosomes Responsible for the Selective Uptake and Degradation of Cytosolic Proteins*

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Two populations of rat liver lysosomes can be distinguished on the basis of their density. A major difference between these populations is that one contains the heat shock cognate protein of 73 kDa (hsc73) within the lysosomal lumen. The lysosomal fraction containing hsc73 exhibits much higher efficiencies in the in vitro uptake and degradation of glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A, two well established substrates of the selective lysosomal pathway of intracellular protein degradation. Preloading of the lysosomal population that is devoid of lumenal hsc73 with hsc73 isolated from cytosol activated the selective transport of substrate proteins into these lysosomes. Furthermore, treatment of animals with leupeptin, an inhibitor of lysosomal cathepsins, or 88 h of starvation also increased the amount of hsc73 within their lysosomal lumen, and these in vivo treatments also activated the selective transport of substrate proteins in vitro. Thus, the hsc73 located within lysosomes appears to be required for efficient uptake of cytosolic proteins by these organelles. The difference in hsc73 content between the lysosomal populations appears to be due to differences in their ability to take up hsc73 combined with differences in the intralysosomal degradation rates of hsc73. The increased stability of hsc73 in one population of lysosomes is primarily a consequence of this lysosomal population's more acidic pH.

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*

This work was supported by a post-doctoral grant Fundacion Ramon Areces (Spain) (to A. M. C.), by National Institutes of Health Grant AG06116 (to J. F. D.), and by Dirección General de Investigación Científica y Técnica del Ministerio de Educación y Ciencia Grant PB94-1281 and Fondo de Investigación Sanitaria de la Seguridad Social 93/0498 (to E. K.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

The abbreviations used are:

    RNase A

    ribonuclease A

    RNase S-peptide

    residues 1-20 of RNase A

    GAPDH

    glyceraldehyde-3-phosphate dehydrogenase

    hsc73

    heat shock cognate protein of 73 kDa

    hsp70

    heat shock protein of 70 kDa

    FITC

    fluorescein isothiocyanate

    lgp120

    lysosomal glycoprotein of 120 kDa

    GST

    glutathione transferase

    MOPS

    3-(N-morpholino) propanesulfonic acid

    PAGE

    polyacrylamide gel electrophoresis.