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J. Biol. Chem., Vol. 276, Issue 22, 19126-19131, June 1, 2001
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From the ¶ Renal Division, Department of Medicine, Emory
University School of Medicine, Atlanta, Georgia and the
Growth factors suppress the degradation of
cellular proteins in lysosomes in renal epithelial
cells. Whether this process also involves specific classes of
proteins that influence growth processes is unknown. We investigated
chaperone-mediated autophagy, a lysosomal import pathway that depends
on the 73-kDa heat shock cognate protein and allows the degradation of
proteins containing a specific lysosomal import consensus sequence
(KFERQ motif). Epidermal growth factor (EGF) or ammonia, but not
transforming growth factor
A Mechanism Regulating Proteolysis of Specific Proteins during
Renal Tubular Cell Growth*
§¶,, and Atlanta Veterans Affairs Medical Center,
Decatur, Georgia 30033
1, suppresses total protein breakdown in
cultured NRK-52E renal epithelial cells. EGF or ammonia prolonged the
half-life of glyceraldehyde-3-phosphate dehydrogenase, a classic
substrate for chaperone-mediated autophagy, by more than 90%, whereas
transforming growth factor 1 did not. EGF caused a similar increase
in the half-life of the KFERQ-containing paired box-related
transcription factor, Pax2. The increase in half-life was accompanied
by an increased accumulation of proteins with a KFERQ motif including glyceraldehyde-3-phosphate dehydrogenase and Pax2. Ammonia also increased the level of the Pax2 protein. Lysosomal import of KFERQ proteins depends on the abundance of the 96-kDa lysosomal glycoprotein protein (lgp96), and we found that EGF caused a significant decrease in
lgp96 in cellular homogenates and associated with lysosomes. We
conclude that EGF in cultured renal cells regulates the breakdown of
proteins targeted for destruction by chaperone-mediated
autophagy. Because suppression of this pathway results in an
increase in Pax2, these results suggest a novel mechanism for the
regulation of cell growth.
*
This work was supported by National Institutes of Health K08
DK02496 a Young Investigator Research Grant from the National Kidney
Foundation, a Veterans Administration Merit Review Award (to H. F.),
an American Heart Association Scientist Development Award (to J. D.),
and a fellowship grant from the National Kidney Foundation of Georgia
(to S. S.).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.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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