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J. Biol. Chem., Vol. 278, Issue 28, 26166-26173, July 11, 2003

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Islet Cell Autoantigen of 69 kDa Is an Arfaptin-related Protein Associated with the Golgi Complex of Insulinoma INS-1 Cells^*

Folker Spitzenberger    ¶, Susan Pietropaolo ||, Paul Verkade **, Bianca Habermann , Sandra Lacas-Gervais , Hassan Mziaut , Massimo Pietropaolo || and Michele Solimena   ** 

From the Experimental Diabetology and the Department of Internal Medicine III, "Carl Gustav Carus" Medical School, University of Technology Dresden, 01307 Dresden, Germany, the ^||Division of Immunogenetics, Diabetes Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, the ^**Max Planck Institute for Molecular Cell Biology and Genetics, 01307 Dresden, Germany, and Scionics GmbH, 01307 Dresden, Germany

Islet cell autoantigen of 69 kDa (ICA69) is a cytosolic protein of still unknown function. Involvement of ICA69 in neurosecretion has been suggested by the impairment of acetylcholine release at neuromuscular junctions upon mutation of its homologue gene ric-19 in C. elegans. In this study, we have further investigated the localization of ICA69 in neurons and insulinoma INS-1 cells. ICA69 was enriched in the perinuclear region, whereas it did not co-localize with markers of synaptic vesicles/synaptic-like microvesicles. Confocal microscopy and subcellular fractionation in INS-1 cells showed co-localization of ICA69 with markers of the Golgi complex and, to a minor extent, with immature insulin-containing secretory granules. The association of ICA69 with these organelles was confirmed by immunoelectron microscopy. Virtually no ICA69 immunogold labeling was observed on secretory granules near the plasma membrane, suggesting that ICA69 dissociates from secretory granule membranes during their maturation. In silico sequence and structural analyses revealed that the N-terminal region of ICA69 is similar to the region of arfaptins that interacts with ARF1, a small GTPase involved in vesicle budding at the Golgi complex and immature secretory granules. ICA69 is therefore a novel arfaptin-related protein that is likely to play a role in membrane trafficking at the Golgi complex and immature secretory granules in neurosecretory cells.

Received for publication, December 27, 2002 , and in revised form, March 24, 2003.

^* This work was supported by grants from the National Institutes of Health (to M. S. and M. P.), the American Diabetes Association (to M. S. and M. P.), and the Alexander von Humboldt Foundation (to M. S.). 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.

^¶ Recipient of a Meddrive grant of the Medical School at the University of Technology Dresden.

To whom correspondence should be addressed: Experimental Diabetology, "Carl Gustav Carus" Medical School, University of Technology Dresden, Fetscherstr. 74, 01307 Dresden, Germany. Tel.: 49-351-458-6611; Fax: 49-351-458-6330; E-mail: michele.solimena{at}mailbox.tu-dresden.de.

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