Processing and targeting of granule proteins in human neutrophils

Neutrophils contain an assembly of granules destined for regulated secretio n, each granule type with distinct constituents formed before terminal diff erentiation. The earliest granules are designated azurophil (primary), foll owed in time by specific (secondary), and gelatinase granules as well as se cretory vesicles. Transcription factors regulate the genes for the granule proteins to ensure that expression of the gene products to be stored in dif ferent organelles is separated in time. Similar to lysosomal enzymes, many granule proteins, in particular those of the heterogeneous azurophil granul es, are trimmed by proteolytic processing into mature proteins. Rodent myel oid cell lines have been utilized for research on the processing and target ing of human granule proteins after transfection of cDNA. Results from exte nsive work on the hematopoietic serine proteases of azurophil granules, emp loying in vitro mutagenesis, indicate that both an immature and a mature co nformation are compatible with targeting for storage in granules. On the ot her hand, the amino-terminal propeptide of myeloperoxidase facilitates both the export from the endoplasmic reticulum and targeting for storage in gra nules. Similarly, targeting of defensins rely on an intact propeptide. The proteolytic processing into mature granule protein is most commonly a post- sorting event, Mis-sorting of specific granule proteins into azurophil or l ysosome-like granules can result in premature activation and degradation, b ut represents a potential for manipulating the composition and function of neutrophil granules. (C) 1999 Elsevier Science B.V. All rights reserved.