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Vol. 15, Issue 4, 1690-1701, April 2004

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Syntaxin-6 SNARE Involvement in Secretory and Endocytic Pathways of Cultured Pancreatic -Cells

Regina Kuliawat ^*, Elena Kalinina , Jason Bock , Lloyd Fricker , Timothy E. McGraw , Se Ryoung Kim ^*, Jiayu Zhong ^*, Richard Scheller ^||, and Peter Arvan ^¶ #

^* Division of Endocrinology and Department of Developmental/Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461; Human Genome Sciences, Inc., Rockville, Maryland 20850; Department of Biochemistry and Structural Biology, Weill Medical College of Cornell University, New York, New York 10021; ^|| Genentech, Inc., South San Francisco, California 94080; and ^¶ Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Submitted August 4, 2003; Revised December 1, 2003; Accepted January 6, 2004
Monitoring Editor: Benjamin Glick

In pancreatic -cells, the syntaxin 6 (Syn6) soluble N-ethylmaleimide-sensitive factor attachment protein receptor is distributed in the trans-Golgi network (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 occurs 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 is affected. Biosynthetic effects of dominant-interfering Syn6 seem 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.

^# Corresponding author. E-mail address: parvan{at}umich.edu.

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