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J. Biol. Chem., Vol. 278, Issue 34, 31486-31494, August 22, 2003

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The Trafficking of ₁-Antitrypsin, a Post-Golgi Secretory Pathway Marker, in INS-1 Pancreatic Beta Cells^*

Lijun Feng and Peter Arvan 

From the Division of Endocrinology and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461

A sulfated ₁-antitrypsin (AAT), thought to be a default secretory pathway marker, is not stored in secretory granules when expressed in neuroendocrine PC12 cells. In search of a constitutive secretory pathway marker for pancreatic beta cells, we produced INS-1 cells stably expressing wild-type AAT. Because newly synthesized AAT arrives very rapidly in the Golgi complex, kinetics alone cannot resolve AAT release via distinct secretory pathways, although most AAT is secreted within a few hours and virtually none is stored in mature granules. Nevertheless, from pulse-chase analyses, a major fraction of newly synthesized AAT transiently exhibits secretogogue-stimulated exocytosis and localizes within immature secretory granules (ISGs). This trafficking occurs without detectable AAT polymerization or binding to lipid rafts. Remarkably, in a manner not requiring its glycans, all of the newly synthesized AAT is then removed from granules during their maturation, leading mostly to constitutive-like AAT secretion, whereas a smaller fraction (10%) goes on to lysosomes. Secretogogue-stimulated ISG exocytosis reroutes newly synthesized AAT directly into the medium and prevents its arrival in lysosomes. These data are most consistent with the idea that soluble AAT abundantly enters ISGs and then is efficiently relocated to the endosomal system, from which many molecules undergo constitutive-like secretion while a smaller fraction advances to lysosomes.

Received for publication, May 30, 2003

^* This work was supported by National Institutes of Health Grant DK48280, an American Diabetes Association mentor-based postdoctoral award, and a grant from the AlphaOne Foundation (all to P. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Endocrinology, University of Michigan, MSRB2 Rm. 5560, 1500 W. Medical Center Dr., Ann Arbor, MI 48109. Tel.: 734-936-5505; Fax: 734-651-4499; E-mail: parvan{at}umich.edu.

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