Secretogranins I and I1: Two Tyrosine-Sulfated Secretory Proteins Common to a Variety of Cells Secreting Peptides by the Regulated Pathway

We report on the biochemical and immunological properties as well as on the cellular and subcellular distribution of two proteins, called secretogranins I and II. These proteins specifically occur in a wide variety of endocrine and neuronal cells that package and sort regulatory peptides into secretory granules. Both secretogranins take the same intracellular route as the peptides and are also sorted into secretory granules. Secretogranins I and II are biochemically and immunologically distinct proteins and differ from chromogranin A. Yet, these three proteins are similar to each other in many respects and therefore constitute one class of proteins. A remarkable feature of this protein class is a very acidic pl, brought about by a high content of acidic amino acids as well as by phosphorylation on serine and sulfation on tyrosine and O-linked carbohydrate. As a result, this class of proteins has a high net negative charge even at the acidic pH of the trans Golgi cisternae. We discuss the possibility that this property of the proteins may point to a role in the packaging of regulatory peptides into secretory granules. The intracellular process by which peptide hormones and neuropeptides are secreted has been intensively studied, and many aspects of this process have been characterized (for reviews see references 6, 14, and 43). However, some important questions have remained unanswered, such as how peptides that are secreted by the regulated pathway (16, 32) are packaged and sorted into secretory granules. It can be expected that the identification of specific features of the secretory process that are common to endocrine and neuronal cells, irrespective of the specific peptide secreted, will help to elucidate the unknown mechanisms of packaging and sorting of regulatory peptides. We have been interested (a) in posttranslational modifications that specifically take place at the intraceUular sites where packaging and sorting of peptides are known to occur, and (b) in the possible existence of target proteins for these modifications that are common to different peptide-secreting enThe present address for P. Rosa, A. Hille, R. W. H. Lee, and W. B. Huttner is European Molecular Biology Laboratory, D-6900 Heidelberg, Federal Republic of Germany. THe JOURNAL OF CELL BIOLOGY . VOLUMe 101 NOVEMBER 1985 1999-2011 © The Rockefeller University Press • 0021-9525/85/11[1999/13 $1.00 docrine and neuronal cells. Previous work has shown that the covalent modification of secretory proteins by sulfation of tyrosine (18, 20) apparently occurs in the Golgi complex at the level of the trans cisternae (28; Baeuerle, P. A., and W. B. Huttner, unpublished observations). The search for the major tyrosine-sulfated proteins in a model neurosecretory cell line, the rat pheochromocytoma cell PC 12, led to the identification of two previously uncharacterized secretory proteins, one consisting of a pair of homologous polypeptides of 113/105 kD, and the other one consisting of a pair of homologous polypeptides of 86/84 kD (27). Other studies, investigating sulfated macromolecules in secretory granules, led to the identification of a previously unknown secretory protein of the bovine anterior pituitary (36, 48). An immunologically related protein appeared to be present in the adrenal medulla (37), the tissue from which PC12 cells are derived. We have recently shown that the anterior pituitary protein also consists of a pair of homologous polypeptides of 86/84 kD that contain the sulfate bound to tyrosine residues. These results suggested that the 86/84-kD 1999 on A ril 0, 2017 D ow nladed fom Published November 1, 1985