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Vol. 11, Issue 10, 3277-3288, October 2000
and
*Departments of Pediatrics and Immunology, University of Toronto,
The Hospital for Sick Children, Research Institute, Toronto, Ontario,
Canada M5G 1X8; ICA69 is a diabetes autoantigen with no homologue of known
function. Given that most diabetes autoantigens are associated with
neuroendocrine secretory vesicles, we sought to determine if this is
also the case for ICA69 and whether this protein participates in the
process of neuroendocrine secretion. Western blot analysis of ICA69
tissue distribution in the mouse revealed a correlation between
expression levels and secretory activity, with the highest expression
levels in brain, pancreas, and stomach mucosa. Subcellular fractionation of mouse brain revealed that although most of the ICA69
pool is cytosolic and soluble, a subpopulation is membrane-bound and
coenriched with synaptic vesicles. We used immunostaining in the HIT
insulin-secreting Department of Molecular and Medical
Genetics, University of Toronto, Toronto, Ontario, Canada, M5S 1A8; and
Division of Molecular Biology, The Netherlands Cancer
Institute, 1066 CX Amsterdam, The Netherlands
-cell line to show that ICA69 localizes in a
punctate manner distinct from the insulin granules, suggesting an
association with the synaptic-like microvesicles found in these cells.
To pursue functional studies on ICA69, we chose to use the model
organism Caenorhabditis elegans, for which a homologue of ICA69 exists. We show that the promoter of the C.
elegans ICA69 homologue is specifically expressed in all
neurons and specialized secretory cells. A deletion mutant was isolated
and found to exhibit resistance to the drug aldicarb (an inhibitor of
acetylcholinesterase), suggesting defective neurotransmitter secretion
in the mutant. On the basis of the aldicarb resistance phenotype, we
named the gene ric-19 (resistance to inhibitors of
cholinesterase-19). The resistance to aldicarb was rescued by
introducing a ric-19 transgene into the
ric-19 mutant background. This is the first study aimed at dissecting ICA69 function, and our results are consistent with the
interpretation that ICA69/RIC-19 is an evolutionarily conserved cytosolic protein participating in the process of neuroendocrine secretion via association with certain secretory vesicles.
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