DNA Strongly Impairs the Inhibition of Cathepsin G by α1-Antichymotrypsin and α1-Proteinase Inhibitor

Duranton, Jérôme; Boudier, Christian; Belorgey, Didier; Mellet, Philippe; Bieth, Joseph G.

doi:10.1074/jbc.275.6.3787

Cited by 29 publications

(29 citation statements)

References 22 publications

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“…In contrast, antithrombin inhibits FSAP only in the presence of heparin (9). Our data contrast sharply with observations made concerning the effect of DNA on the interactions between cathepsin G and ␣ 1 -antichymotrypsin and between cathepsin G and ␣ 1 -proteinase inhibitor (38), where cathepsin G-DNA complexes were resistant to the inhibition by ␣ 1 -antichymotrypsin and ␣ 1 -proteinase inhibitor. It remains unclear why RNA is a much better enhancer of the FSAP-PAI-1 interaction than is DNA, although it might be speculated that singlestranded RNA is less sterically constrained than is doublestranded DNA.…”

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confidence: 57%

“…Other reports have demonstrated that double-stranded nucleic acids prevent the inhibition of serine proteinases (such as cathepsin G) by their cognate serpins, including ␣ 1 -proteinase inhibitor and ␣ 1 -antichymotrypsin (37,38). Therefore, we felt it relevant to explore whether the presence of large amounts of extracellular RNA impacted the FSAP-PAI-1 interaction.…”

Section: Figure 4 Pai-1 Does Not Form Complexes With Single-chain Fsapmentioning

confidence: 99%

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Plasminogen Activator Inhibitor-1 Is an Inhibitor of Factor VII-activating Protease in Patients with Acute Respiratory Distress Syndrome

Wygrecka

Morty

Markart

et al. 2007

Journal of Biological Chemistry

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Factor VII-activating protease (FSAP) is a novel plasma-derived serine protease structurally homologous to tissue-type and urokinase-type plasminogen activators. We demonstrate that plasminogen activator inhibitor-1 (PAI-1), the predominant inhibitor of tissue-type and urokinase-type plasminogen activators in plasma and tissues, is an inhibitor of FSAP as well. We detected PAI-1⅐FSAP complexes in addition to high levels of extracellular RNA, an important FSAP cofactor, in bronchoalveolar lavage fluids from patients with acute respiratory distress syndrome. Hydrolytic activity of FSAP was inhibited by PAI-1 with a second-order inhibition rate constant (K a ) of 3.38 ؎ Factor VII-activating protease (FSAP), 2 also known as plasma hyaluronan-binding protein or plasma hyaluronanbinding serine protease, is a recently described plasma serine protease (1-3), expressed primarily in the liver and found in endothelial and epithelial cells of the lung, kidney, placenta, and pancreas (1, 4). The enzyme circulates as a 64-kDa single-chain zymogen (scFSAP) in plasma, which is autoactivated to an enzymatically active two-chain form (tcFSAP). Two-chain FSAP consists of a 46-kDa heavy chain connected by a disulfide bridge to a 29-kDa light chain containing the catalytic domain (5-7). Autoactivation of scFSAP to tcFSAP is promoted in the presence of negatively charged substances, such as heparin, dextran sulfate, phosphatidylethanolamine, or extracellular RNA (5-8).The role of FSAP in different physiological and pathophysiological conditions is not fully understood. A dual role for FSAP in vitro in hemostasis has been suggested (3, 9). FSAP is a potent activator of coagulation factor VII, thus contributing to the initiation of blood coagulation via the extrinsic pathway (3). Furthermore, FSAP also activates prourokinase-type plasminogen activator (uPA) and thus contributes to plasminogen activation as well (9). Additional links between FSAP and the plasminogen activation system exist; FSAP is highly homologous to uPA and tissue-type plasminogen activator (tPA), and uPA is a potential physiological activator of FSAP (5). Additionally, recent in vitro studies have revealed that hemostatic serine protease inhibitors (serpins), such as C1 inhibitor and ␣ 2 -antiplasmin, are inhibitors of FSAP proteolytic activity (7, 9). These observations prompted us to explore the role of PAI-1, the primary member of this inhibitor family in plasma and tissues (10, 11), as a potential regulator of FSAP. It is known that PAI-1 inhibits uPA and tPA by forming SDS-resistant, catalytically inactive complexes with proteases (12, 13). In this reaction, the reactive center residues P 1 -P 1 Ј (Arg 346 -Met 347 ) in PAI-1 function as an exposed "bait" for the protease by mimicking a putative cleavage site (14 -17). In addition to inhibiting serine proteases, PAI-1 also interacts with different components of the extracellular matrix, including heparin (18, 19) and vitronectin (20 -22). In the presence of heparin, the selectivity of PAI-1 for the inhibition ...

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confidence: 57%

Section: Figure 4 Pai-1 Does Not Form Complexes With Single-chain Fsapmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 Is an Inhibitor of Factor VII-activating Protease in Patients with Acute Respiratory Distress Syndrome

Wygrecka

Morty

Markart

et al. 2007

Journal of Biological Chemistry

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“…Several members of the metalloproteinase family, including collagenase, matrix metalloproteinase 9 and Pseudomonas elastase, and of the thiol protease family can cleave and inactivate AT [49]. Third, DNA, which often is released from neutrophils at sites of inflammatory activation and phagocytosis, can impair the cathepsin G inhibitory activity of AT [50].…”

Section: Function Of Atmentioning

confidence: 99%

α1-Antitrypsin Deficiency

Perlmutter

2010

Molecular Pathology Library

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“…3a). To identify the key proteinase involved in the decrease of IL-22R expression, we repeated this experiment with a more specific inhibitor, ACT, which reacts only with CG [18]. Interestingly, ACT prevented the disappearance of IL-22R1 signal, suggesting a prominent role for CG in this process ( fig.…”

Section: Effect Of Neutrophil Serine Proteinases On Il-22r Expressionmentioning

confidence: 99%

Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence

et al. 2015

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Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infectiondriven acute exacerbations. Despite the life-threatening nature of these exacerbations, the underlying mechanisms remain unclear, although a high number of neutrophils in the lungs of COPD patients is known to correlate with poor prognosis. Interleukin (IL)-22 is a cytokine that plays a pivotal role in lung antimicrobial defence and tissue protection. We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.Using in vitro and in vivo approaches as well as reverse transcriptase quantitative PCR, flow cytometry and/or Western blotting techniques, we first showed that pathogens such as the influenza virus promote IL-22R expression in human bronchial epithelial cells, whereas Pseudomonas aeruginosa, bacterial lipopolysaccharide or cigarette smoke do not. Most importantly, neutrophil proteases cleave IL-22R and impair IL-22-dependent immune signalling and expression of antimicrobial effectors such as β-defensin-2. This proteolysis resulted in the release of a soluble fragment of IL-22R, which was detectable both in cellular and animal models as well as in sputa from COPD patients with acute exacerbations.Hence, our study reveals an unsuspected regulation by the proteolytic action of neutrophil enzymes of IL-22-dependent lung host response. This process probably enhances pathogen replication, and ultimately COPD exacerbations. @ERSpublications Neutrophil proteases alter lung antimicrobial defence and may predispose to infection-triggered COPD exacerbations http://ow.ly/MHqEt

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DNA Strongly Impairs the Inhibition of Cathepsin G by α1-Antichymotrypsin and α1-Proteinase Inhibitor

Cited by 29 publications

References 22 publications

Plasminogen Activator Inhibitor-1 Is an Inhibitor of Factor VII-activating Protease in Patients with Acute Respiratory Distress Syndrome

Plasminogen Activator Inhibitor-1 Is an Inhibitor of Factor VII-activating Protease in Patients with Acute Respiratory Distress Syndrome

α1-Antitrypsin Deficiency

Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence

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