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Posttranslational processing of defensins in immature human myeloid cells
EV Valore and T Ganz
Will Rogers Institute Pulmonary Research Laboratory, University of
California, Los Angeles.
Human neutrophil promyelocytes synthesize, process, and package several
microbicidal proteins, including the highly abundant defensins, into their
azurophil granules. As deduced from their cDNA sequences, defensins are
initially synthesized as 94 amino acid (aa) precursors that must undergo
extensive processing. We performed metabolic labeling studies of defensin
synthesis in the human promyelocytic cell line HL- 60 and in chronic
myeloid leukemia cells, and showed that preprodefensins are processed to
mature 29 to 30 aa defensins over 4 to 24 hours via two major
intermediates: a 75 aa prodefensin generated by the cleavage of the signal
sequence, and a 56 aa prodefensin that results from a subsequent
preaspartate proteolytic cleavage. Almost all of the 75 aa form was found
in the cytoplasmic/microsomal fraction, whereas the 56 aa prodefensin and
mature defensins predominated in the granule-enriched fraction. The 75 aa
prodefensin was also selectively released into the culture supernatant.
Treatment of HL-60 cells with monensin, chloroquine, or ammonium chloride,
substances that neutralize acidic subcellular compartments, partially
blocked conversion of the 75 aa prodefensin into 56 aa prodefensin, but did
not increase the extracellular release of the 75 aa form. Further studies
will be required to determine the role of this processing pathway in
subcellular targeting to azurophil granules and avoidance of
autocytotoxicity.
Volume 79,
Issue 6,
pp. 1538-1544,
03/15/1992
Copyright © 1992 by The American Society of Hematology
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