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Roles of heme insertion and the mannose-6-phosphate receptor in processing
of the human myeloid lysosomal enzyme, myeloperoxidase
WM Nauseef, S McCormick and H Yi
Department of Medicine, College of Medicine, University of Iowa, Iowa City
52242.
Biosynthesis of myeloperoxidase (MPO), a myeloid lysosomal hemoprotein
critical for the optimal oxygen-dependent microbicidal activity of human
neutrophils, is incompletely understood. The primary translation product
undergoes cotranslational N-linked glycosylation with subsequent insertion
of the Fe-containing prosthetic group into the peptide backbone, thereby
converting the enzymatically inactive, heme- free apoproMPO into the
peroxidatively active precursor, proMPO. Eventually, proMPO undergoes
proteolytic processing into native, lysosomal MPO, with subunits of 59 and
13.5 Kd. We studied three unanswered questions regarding MPO biosynthesis:
(1) At what point during MPO biosynthesis is the heme moiety inserted into
the apoenzyme? (2) What consequences does heme-insertion have on subsequent
processing events? (3) What role does the mannose-6-phosphate receptor
(M6PR) system play in the delivery of MPO to the lysosome? Disruption of
Golgi by brefeldin A (BFA) produced two major changes in MPO biosynthesis:
(1) processing of the 89-Kd precursor to mature MPO was blocked and (2)
constitutive secretion of the MPO precursor was inhibited. Inhibition of
heme synthesis with succinyl acetone (SA) reduced peroxidase activity and
profoundly blocked processing of proMPO to mature MPO. This inhibition of
processing was not a generalized effect on all lysosomal enzymes, because
the maturation of a non-heme-containing lysosomal enzyme,
beta-glucuronidase, was not altered. Electron microscopy showed that,
although the normal peroxidase staining of endoplasmic reticulum was absent
in SA-treated cells, there were MPO- related peptides in the ER. The role
of the M6PR system was assessed by immunoprecipitating fractions obtained
from M6PR affinity column chromatography. The 89-Kd proMPO failed to adhere
to the M6PR affinity column, whereas the 59-Kd heavy subunit of mature MPO
was specifically eluted from the column. We interpret these data to
indicate that: (1) processing of proMPO to mature MPO occurs in a post-ER
compartment that is itself BFA-sensitive or is distal to a BFA-sensitive
compartment and (2) heme insertion into apoproMPO precedes and may be a
prerequisite for proteolytic processing to enzymatically active mature MPO.
Our analysis of the M6PR system in MPO biosynthesis led to the
unanticipated finding that there were phosphomannosyl residues on mature
MPO, but none on proMPO. We suggest that the bulk of proMPO at any time is
not phosphorylated, but, when generated, the phosphorylated proMPO is
quickly processed to the phosphorylated 59-Kd subunit of mature MPO. Thus,
if the M6PR is important in the intracellular transport of MPO, it is the
phosphorylated mature MPO that is directed to the lysosomal compartment by
this system.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 80,
Issue 10,
pp. 2622-2633,
11/15/1992
Copyright © 1992 by The American Society of Hematology
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