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A more recent version of this article appeared on April 1, 2004
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Submitted on August 4, 2003
Revised on December 1, 2003
Accepted on January 6, 2004
1 Division of Endocrinology and Department of Developmental/Molecular Biology, Albert Einstein College of Medicine, Bronx NY 10461
2 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx NY 10461
3 Human Genome Sciences, Inc., Rockville, MD 20850
4 Department of Biochemistry and Structural Biology, Weill Medical College of Cornell University, New York NY 10021
5 Genentech, Inc., South San Francisco CA 94080
6 Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor MI 48109
* Corresponding author. E-mail address: parvan{at}umich.edu.
In pancreatic 
-cells the syntaxin 6 (Syn6) SNARE is distributed in the TGN (with spillover into immature secretory granules) and endosomes. A possible Syn6 requirement has been suggested in secretory granule biogenesis, but the role of Syn6 in live regulated secretory cells remains unexplored. We have created an ecdysone-inducible gene expression system in the INS-1 -cell line and find that induced expression of a membrane-anchorless, cytosolic Syn6 (called Syn6t), but not full-length Syn6, causes a prominent defect in endosomal delivery to lysosomes, and the TGN, in these cells. The defect appears downstream of the endosomal branchpoint involved in transferrin recycling, and upstream of the steady-state distribution of mannose 6-phosphate receptors. By contrast, neither acquisition of stimulus-competence nor the ultimate size of -granules are affected. Biosynthetic effects of dominant-interfering Syn6 appear limited to slowed intragranular processing to insulin (achieving normal levels within 2 h) and minor perturbation of sorting of newly-synthesized lysosomal proenzymes. We conclude that expression of the Syn6t mutant slows a rate-limiting step in endosomal maturation but provides only modest and potentially indirect interference with regulated and constitutive secretory pathways, and in TGN sorting of lysosomal enzymes.
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