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Vol. 8, Issue 11, 2171-2185, November 1997
Department of Molecular and Cell Biology, University of
California, Berkeley, California 94720-3200
The biogenesis of peptide hormone secretory granules
involves a series of sorting, modification, and trafficking steps that initiate in the trans-Golgi and
trans-Golgi network (TGN). To investigate their temporal
order and interrelationships, we have developed a pulse-chase protocol
that follows the synthesis and packaging of a sulfated hormone,
pro-opiomelanocortin (POMC). In AtT-20 cells, sulfate is incorporated
into POMC predominantly on N-linked endoglycosidase H-resistant
oligosaccharides. Subcellular fractionation and pharmacological studies
confirm that this sulfation occurs at the
trans-Golgi/TGN. Subsequent to sulfation, POMC undergoes a number of molecular events before final storage in dense-core granules. The first step involves the transfer of POMC from the sulfation compartment to a processing compartment (immature secretory granules, ISGs): Inhibiting export of pulse-labeled POMC by brefeldin A
(BFA) or a 20°C block prevents its proteolytic conversion to mature
adrenocorticotropic hormone. Proteolytic cleavage products were found
in vesicular fractions corresponding to ISGs, suggesting that the
processing machinery is not appreciably activated until POMC exits the
sulfation compartment. A large portion of the labeled hormone is
secreted from ISGs as incompletely processed intermediates. This
unregulated secretory process occurs only during a limited time window:
Granules that have matured for 2 to 3 h exhibit very little
unregulated release, as evidenced by the efficient storage of the
15-kDa N-terminal fragment that is generated by a relatively late
cleavage event within the maturing granule. The second step of granule
biogenesis thus involves two maturation events: proteolytic activation
of POMC in ISGs and a transition of the organelle from a state of high
unregulated release to one that favors intracellular storage. By using
BFA, we show that the two processes occurring in ISGs may be uncoupled:
although the unregulated secretion from ISGs is impaired by BFA,
proteolytic processing of POMC within this organelle proceeds
unaffected. The finding that BFA impairs constitutive secretion from
both the TGN and ISGs also suggests that these secretory processes may
be related in mechanism. Finally, our data indicate that the unusually
high levels of unregulated secretion often associated with endocrine
tumors may result, at least in part, from inefficient storage of
secretory products at the level of ISGs.
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