Degradation of Outer Membrane Protein A in
            <i>Escherichia coli</i>
            Killing by Neutrophil Elastase

Belaaouaj, Abderrazzaq; Kim, Kwang Sik; Shapiro, Steven D.

doi:10.1126/science.289.5482.1185

Cited by 327 publications

(264 citation statements)

References 15 publications

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“…Elastase degrades the outer membrane protein A of E. coli, which is located on the surface of the bacteria [11,250]. Mice lacking PMN elastase and other granule-proteases are more sensitive to E. coli infection [10] and other bacterial and fungal infections [194].…”

Section: Non-oxidative Mechanisms Of E Coli Killingmentioning

confidence: 99%

Severity of E. coli mastitis is mainly determined by cow factors

et al. 2003

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-Intramammary infections of dairy cows with Gram-positive bacteria such as Staphylococcus aureus (major cause of mastitis) have received a lot of attention because of their major economic impact on the dairy farm through production losses induced by an increase in somatic cell count. Management strategies, including greater awareness for efficient milking and hygienic measures, have limited the spread of Gram-positive bacteria and resulted in a significant decrease of proportion of S. aureus isolates and subclinical mastitis worldwide. Other organisms such as coliform subspecies and Streptococcus uberis, both environmental bacteria that cause clinical mastitis, have received less attention. Escherichia coli causes inflammation of the mammary gland in dairy cows around parturition and during early lactation with striking local and sometimes severe systemic clinical symptoms. This disease affects many high producing cows in dairy herds and may cause several cases of death per year in the most severe cases. It is well known that bacterial, cow and environmental factors are interdependent and influence mastitis susceptibility. Many studies, executed during the last decade, indicate that the severity of E. coli mastitis is mainly determined by cow factors rather than by E. coli pathogenicity. During E. coli mastitis, the host defense status is a cardinal factor determining the outcome of the disease. Today, we know that the neutrophil is a key factor in the cows' defense against intramammary infection with E. coli. Effective elimination of the pathogen by neutrophils is important for the resolution of infection and the outcome of E. coli mastitis. This review is a compilation of some major findings over the last 15 years concerning mainly host factors that modulate and influence neutrophil function and the mammary inflammatory reaction. The individual chapters address: virulence factors of E. coli strains, how neutrophils kill E. coli, connection between endotoxins, tumor necrosis factor-a and nitric oxide, severity classification of E. coli mastitis, lifespan of neutrophils, host factors that influence severity, tissue damage and production loss.

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Section: Non-oxidative Mechanisms Of E Coli Killingmentioning

confidence: 99%

Severity of E. coli mastitis is mainly determined by cow factors

et al. 2003

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“…The HNE also acts extracellularly, particularly at sites of inflammation [Weiss, 1989]. The human neutrophil elastase degrades not only elastin, but also various other tissue proteins such as collagens, proteoglycans, and plasma factors like fibrinogen, fibrin, and antithrombin III [Wintroub et al, 1980;Bach-Gansmo et al, 1996;Gillis et al, 1997], and bacteria virulence proteins [Belaaouaj et al, 2000;Weinrauch et al, 2002]. A recently described novel mechanism explains how neutrophils release granule proteins and chromatin, which together form extracellular fibers to bind and kill bacteria [Brinkmann et al, 2004].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Thusberg

Vihinen

2006

Hum. Mutat.

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For the Immunogenetics Special IssueCyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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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Degradation of Outer Membrane Protein A in Escherichia coli Killing by Neutrophil Elastase

Cited by 327 publications

References 15 publications

Severity of E. coli mastitis is mainly determined by cow factors

Severity of E. coli mastitis is mainly determined by cow factors

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

The tetraspanin CD63 is involved in granule targeting of neutrophil elastase

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