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-Cells
* Diabetes Research Center and Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York 10461; In cells specialized for secretory granule exocytosis, lysosomal hydrolases may enter the regulated
secretory pathway. Using mouse pancreatic islets and
the INS-1 Research Institute Neurosciences, Vrije Universiteit Faculty of Biology, Amsterdam, The Netherlands; § Department of
Genetics and Development, Columbia University, New York
-cell line as models, we have compared the
itineraries of procathepsins L and B, two closely related
members of the papain superfamily known to exhibit
low and high affinity for mannose-6-phosphate receptors (MPRs), respectively. Interestingly, shortly after
pulse labeling INS cells, a substantial fraction of both
proenzymes exhibit regulated exocytosis. After several
hours, much procathepsin L remains as precursor in a
compartment that persists in its ability to undergo regulated exocytosis in parallel with insulin, while procathepsin B is efficiently converted to the mature form
and can no longer be secreted. However, in islets from
transgenic mice devoid of cation-dependent MPRs, the modest fraction of procathepsin B normally remaining
within mature secretory granules is increased approximately fourfold. In normal mouse islets, immunoelectron microscopy established that both cathepsins are
present in immature -granules, while immunolabeling for cathepsin L, but not B, persists in mature -granules. By contrast, in islets from normal male SpragueDawley rats, much of the proenzyme sorting appears to
occur earlier, significantly diminishing the stimulusdependent release of procathepsin B. Evidently, in the
context of different systems, MPR-mediated sorting of
lysosomal proenzymes occurs to a variable extent
within the trans-Golgi network and is continued, as
needed, within immature secretory granules. Lysosomal proenzymes that fail to be sorted at both sites remain as residents of mature secretory granules.
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