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Cell Biology and Metabolism Branch, National Institite of Child Health and Human Development, National Institutes of Health,
Bethesda, Maryland 20892
The mammalian endopeptidase furin is a
type 1 integral membrane protein that is predominantly
localized to the TGN and is degraded in lysosomes with
a t1/2 = 2-4 h. Whereas the localization of furin to the
TGN is largely mediated by sorting signals in the cytosolic tail of the protein, we show here that targeting of
furin to lysosomes is a function of the luminal domain
of the protein. Inhibition of lysosomal degradation results in the accumulation of high molecular weight aggregates of furin; aggregation is also dependent on the
luminal domain of furin. Temperature and pharmacologic manipulations suggest that furin aggregation occurs in the TGN and thus precedes delivery to lysosomes. These findings are consistent with a model in
which furin becomes progressively aggregated in the
TGN, an event that leads to its transport to lysosomes.
Our observations indicate that changes in the aggregation state of luminal domains can be potent determinants of biosynthetic targeting to lysosomes and suggest the possible existence of quality control mechanisms for disposal of aggregated proteins in compartments of the secretory pathway other than the endoplasmic reticulum.
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