Neutrophil elastase depends on serglycin proteoglycan for localization in granules

Niemann, Carsten Utoft; Åbrink, Magnus; Pejler, Gunnar; Fischer, Rikke L.; Christensen, Erik I.; Knight, Stefan D.; Borregaard, Niels

doi:10.1182/blood-2006-02-001719

Cited by 90 publications

(105 citation statements)

References 60 publications

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“…32 New observations on serglycin knockout support the idea that this proteoglycan has a role in the targeting of NE to primary granules: mature neutrophils of knockout mice lacked NE. 31 The precise mechanism by which the knockout phenotype is formed has not yet been revealed. Collectively, the information available suggests that the disruption of either AP-3, 15,16 serglycin, 31 or NE (by mutations in cyclic neutropenia) 41 may perturb intracellular NE trafficking, suggesting intricate sorting.…”

Section: Discussionmentioning

confidence: 99%

“…31 The precise mechanism by which the knockout phenotype is formed has not yet been revealed. Collectively, the information available suggests that the disruption of either AP-3, 15,16 serglycin, 31 or NE (by mutations in cyclic neutropenia) 41 may perturb intracellular NE trafficking, suggesting intricate sorting. In addition, our findings also suggest that CD63 is involved in proNE trafficking.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 Therefore, the possible presence of proteoglycans was examined, as previously described by Lemansky et al 32 COS cells coexpressing NE and GFP-CD63 were incubated with radioactive sulfate, immunoprecipitated with anti-cproNE, and subjected to SDS-PAGE followed by fluorography. ProNE did not pull down any 35 S-labeled macromolecules (data not shown), indicating that proteoglycan was not present.…”

Section: Prone and Cd63 Colocalize In Cos Cellsmentioning

confidence: 99%

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The tetraspanin CD63 is involved in granule targeting of neutrophil elastase

Källquist

Hansson

Persson

et al. 2008

Blood

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Targeting mechanisms of neutrophil elastase (NE) and other luminal proteins stored in myeloperoxidase (MPO)-positive secretory lysosomes/primary granules of neutrophils are unknown. These granules contain an integral membrane protein, CD63, with an adaptor protein-3-dependent granule delivery system. Therefore, we hypothesized that CD63 cooperates in granule delivery of the precursor of NE (proNE). Supporting this hypothesis, an association was demonstrated between CD63 and proNE upon coexpression in COS cells. This also involved augmented cellular retention of proNE requiring intact large extracellular loop of CD63. Furthermore, depletion of CD63 in promyelocytic HL-60 cells with RNA interference or a CD63 mutant caused reduction of cellular NE. However, the proNE steady-state level was similar to wild type in CD63-depleted clones, making it feasible to examine possible effects of CD63 on NE trafficking. Thus, depletion of CD63 led to reduced processing of proNE into mature NE and reduced constitutive secretion. Furthermore, CD63-depleted cells showed a lack of morphologically normal granules, but contained MPO-positive cytoplasmic vacuoles with a lack of proNE and NE. Collectively, our data suggest that granule proteins may cooperate in targeting; CD63 can be involved in ER or Golgi export, cellular retention, and granule targeting of proNE before storage as mature NE. (Blood. 2008;112:3444-3454) IntroductionHematopoietic cells play a critical role in host defense, for which they are equipped with secretory lysosomes or lysosome-related organelles that can release cell-specific cytolytic proteins by regulated secretion. 1,2 The secretory lysosomes/primary granules of neutrophils are furnished with an array of proteins that includes hematopoietic serine proteases along with myeloperoxidase (MPO), other microbicidal proteins, and specific transmembrane proteins. 3,4 The precise functions of the hematopoietic serine proteases-neutrophil elastase (NE), cathepsin G, proteinase 3, and azurocidin-are not fully known, but all 4 are thought to be important in the innate immunity function provided by neutrophils. 5,6 These proteases are synthesized as transient proforms that become catalytically active (except for azurocidin) by removal of an N-terminal propeptide after granule targeting. 7,8 Lysosome hydrolases and granzymes use a mannose-6-phosphate (MP) signal and binding to an MP receptor for targeting, 9,10 but the signals for the targeting of hematopoietic serine proteases are not yet known. Cargo proteins can be transported to secretory lysosomes independent of the MP system, 11 as is illustrated by the fact that in I-cell disease, neutrophils and other cells have a normal content of hydrolases despite a lack of MP synthesis. 12 The delivery of a soluble protein might occur through the assistance of a cooperating transmembrane partner that establishes contact with adaptor proteins (APs) to recruit the transport system necessary for targeting. The adaptor protein AP-3 is known to have a role in bringing transmembr...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Prone and Cd63 Colocalize In Cos Cellsmentioning

confidence: 99%

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The tetraspanin CD63 is involved in granule targeting of neutrophil elastase

Källquist

Hansson

Persson

et al. 2008

Blood

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“…Serglycin Null allele: viable; secretory granule defects in mast cells (Abrink et al 2004); dense core formation is defective in mast cell granules (Henningsson et al 2006); defective secretory granule maturation and granzyme B storage in cytotoxic T cells (Grujic et al 2005); no effect on macrophages (Zernichow et al 2006); platelets and megakaryocytes contain unusual scroll-like membranous inclusions (Woulfe et al 2008); enlargement of multiple lymphoid organs, decrease in the proportion of CD4 þ cells, more pronounced airway inflammatory response in older mice (Wernersson et al 2009); increased virulence of Klebsiella pneumoniae (Niemann et al 2007); defective regulation of antiviral CD8 þ T-cell responses (Grujic et al 2008). Agrn Agrin Null allele: embryonic lethal; reduced number, size, and density of postsynaptic acetylcholine receptor aggregates in muscles; abnormal intramuscular nerve branching and presynaptic differentiation (Gautam et al 1996(Gautam et al ,1999; smaller brains (Serpinskaya et al 1999); abnormal development of interneuronal synapses (Gingras et al 2007); increased resistance to excitotoxic injury (Hilgenberg et al 2002); reduced number of cortical presynaptic and postsynaptic specializations (Ksiazek et al 2007).…”

Section: Prg1mentioning

confidence: 99%

Heparan Sulfate Proteoglycans

Sarrazin¹,

Lamanna²,

Esko

2011

Cold Spring Harbor Perspectives in Biology

1,223

1,238

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“…[1][2][3] Serglycin mRNA expression has been demonstrated in several myeloid and lymphoid cell lines, [4][5][6][7] and serglycin immunoreactivity has been observed in myeloid cells and cell lines 8,9 as well as in cell lines of lymphoid, mast cell, plasmacytoid and myelomonocytic origin. 10 The function of serglycin in the different types of cells is slowly becoming apparent.…”

Section: Introductionmentioning

confidence: 99%