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Vol. 9, Issue 8, 1995-2010, August 1998
B Is a Substrate for a Selective Pathway of Lysosomal
Proteolysis
and
*Department of Physiology, Tufts University, School of Medicine,
Boston, Massachusetts 02111; and
In lysosomes isolated from rat liver and spleen, a percentage of
the intracellular inhibitor of the nuclear factor Department of Medicine,
Harvard Institutes of Medicine, Beth Israel Deaconess Medical Center,
Boston, Massachusetts 02215
B (IB) can be
detected in the lysosomal matrix where it is rapidly degraded. Levels
of IB are significantly higher in a lysosomal subpopulation that is
active in the direct uptake of specific cytosolic proteins. IB is
directly transported into isolated lysosomes in a process that requires
binding of IB to the heat shock protein of 73 kDa (hsc73), the
cytosolic molecular chaperone involved in this pathway, and to the
lysosomal glycoprotein of 96 kDa (lgp96), the receptor protein in the
lysosomal membrane. Other substrates for this degradation pathway
competitively inhibit IB uptake by lysosomes. Ubiquitination and
phosphorylation of IB are not required for its targeting to
lysosomes. The lysosomal degradation of IB is activated under conditions of nutrient deprivation. Thus, the half-life of a long-lived pool of IB is 4.4 d in serum-supplemented Chinese hamster ovary cells but only 0.9 d in serum-deprived Chinese hamster ovary
cells. This increase in IB degradation can be completely blocked by lysosomal inhibitors. In Chinese hamster ovary cells exhibiting an
increased activity of the hsc73-mediated lysosomal degradation pathway
due to overexpression of lamp2, the human form of lgp96, the
degradation of IB is increased. There are both short- and long-lived
pools of IB, and it is the long-lived pool that is subjected to the
selective lysosomal degradation pathway. In the presence of
antioxidants, the half-life of the long-lived pool of IB is
significantly increased. Thus, the production of intracellular reactive
oxygen species during serum starvation may be one of the mechanisms
mediating IB degradation in lysosomes. This selective pathway of
lysosomal degradation of IB is physiologically important since
prolonged serum deprivation results in an increase in the nuclear
activity of nuclear factor B. In addition, the response of nuclear
factor B to several stimuli increases when this lysosomal pathway
of proteolysis is activated.
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