Book Description

The formation of secretory granules is a poorly understood process in which the proteins of secretory granules must be accurately separated, or "sorted", away from other proteins of the secretory pathway. Unlike many other proteins of the secretory pathway, whose sorting is mediated by cytoplasmic sorting machinery like coatamers/adaptors, the proteins of secretory granules appear to be sorted as a result of their own intrinsic properties, namely to from large aggregates and associate with membranes. Challenging this view, we provide strong evidence that cytoplasmic sorting machinery is required in the sorting of secretory granule cargo to the secretory granules of the ciliate Tetrahymena thermophila. We have used a unique genomic dataset from this organism to screen for novel factors involved in secretory granule biogenesis. From this dataset, we identified the cytoplasmic adaptor protein AP-3 and the transmembrane receptor sortilin. Of the four sortilins encoded in the Tetrahymena genome, we demonstrate that two sortilins are necessary for secretory granule formation. Importantly, these two sortilins are necessary for the sorting of non-aggregating but not aggregating secretory granule proteins. Therefore, our results indicate that secretory granule formation in Tetrahymena relies on dual sorting mechanisms that include a new (sortilin) receptor-dependent mechanism for the sorting of non-aggregating cargo in addition to the previously proposed receptor-independent mechanism for the sorting of aggregating cargo. Since Tetrahymena is very distantly related to the organisms in which secretory granules are primarily studied, our results raise interesting implications about the origin and evolution of these specialized organelles. In particular, our results indicate that the secretory granules of Tetrahymena, and perhaps other organisms, may be related in their biogenesis to lysosome-related organelles.