scholarly journals Protean proteases: at the cutting edge of lung diseases

2017 ◽  
Vol 49 (2) ◽  
pp. 1501200 ◽  
Author(s):  
Clifford Taggart ◽  
Marcus A. Mall ◽  
Gilles Lalmanach ◽  
Didier Cataldo ◽  
Andreas Ludwig ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Serine Protease ◽  
Protease Activity ◽  
Serine Proteases ◽  
Lung Diseases ◽  
Serine Protease Inhibitor ◽  
Matrix Metalloproteases ◽  
Integrative Biology ◽  
Therapeutic Tool ◽  
Serine Protease Activity

Proteases were traditionally viewed as mere protein-degrading enzymes with a very restricted spectrum of substrates. A major expansion in protease research has uncovered a variety of novel substrates, and it is now evident that proteases are critical pleiotropic actors orchestrating pathophysiological processes. Recent findings evidenced that the net proteolytic activity also relies upon interconnections between different protease and protease inhibitor families in the protease web.In this review, we provide an overview of these novel concepts with a particular focus on pulmonary pathophysiology. We describe the emerging roles of several protease families including cysteine and serine proteases.The complexity of the protease web is exemplified in the light of multidimensional regulation of serine protease activity by matrix metalloproteases through cognate serine protease inhibitor processing. Finally, we will highlight how deregulated protease activity during pulmonary pathogenesis may be exploited for diagnosis/prognosis purposes, and utilised as a therapeutic tool using nanotechnologies.Considering proteases as part of an integrative biology perspective may pave the way for the development of new therapeutic targets to treat pulmonary diseases related to intrinsic protease deregulation.

scholarly journals Carbohydrate-controlled serine protease inhibitor (serpin) production in Bifidobacterium longum subsp. longum

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
S. Duboux ◽  
M. Golliard ◽  
J. A. Muller ◽  
G. Bergonzelli ◽  
C. J. Bolten ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Serine Protease ◽  
Serine Proteases ◽  
Intestinal Tract ◽  
Defense Mechanism ◽  
Inflammatory Diseases ◽  
Bifidobacterium Longum ◽  
Serine Protease Inhibitor ◽  
Innate Defense

AbstractThe Serine Protease Inhibitor (serpin) protein has been suggested to play a key role in the interaction of bifidobacteria with the host. By inhibiting intestinal serine proteases, it might allow bifidobacteria to reside in specific gut niches. In inflammatory diseases where serine proteases contribute to the innate defense mechanism of the host, serpin may dampen the damaging effects of inflammation. In view of the beneficial roles of this protein, it is important to understand how its production is regulated. Here we demonstrate that Bifidobacterium longum NCC 2705 serpin production is tightly regulated by carbohydrates. Galactose and fructose increase the production of this protein while glucose prevents it, suggesting the involvement of catabolite repression. We identified that di- and oligosaccharides containing galactose (GOS) and fructose (FOS) moieties, including the human milk oligosaccharide Lacto-N-tetraose (LNT), are able to activate serpin production. Moreover, we show that the carbohydrate mediated regulation is conserved within B. longum subsp. longum strains but not in other bifidobacterial taxons harboring the serpin coding gene, highlighting that the serpin regulation circuits are not only species- but also subspecies- specific. Our work demonstrates that environmental conditions can modulate expression of an important effector molecule of B. longum, having potential important implications for probiotic manufacturing and supporting the postulated role of serpin in the ability of bifidobacteria to colonize the intestinal tract.

scholarly journals Multifaceted Analyses of Epidermal Serine Protease Activity in Patients with Atopic Dermatitis

2020 ◽  
Vol 21 (3) ◽  
pp. 913 ◽  
Author(s):  
Hayato Nomura ◽  
Mutsumi Suganuma ◽  
Takuya Takeichi ◽  
Michihiro Kono ◽  
Yuki Isokane ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Serine Protease ◽  
Protease Activity ◽  
Serine Proteases ◽  
Immunoglobulin E ◽  
Total Serum ◽  
Tape Stripping ◽  
Blood Eosinophil ◽  
Peripheral Blood Eosinophil ◽  
Serine Protease Activity

The serine proteases kallikrein-related peptidase (KLK) 5 and KLK7 cleave cell adhesion molecules in the epidermis. Aberrant epidermal serine protease activity is thought to play an important role in the pathogenesis of atopic dermatitis (AD). We collected the stratum corneum (SC) from healthy individuals (n = 46) and AD patients (n = 63) by tape stripping and then measuring the trypsin- and chymotrypsin-like serine protease activity. We also analyzed the p.D386N and p.E420K of SPINK5 variants and loss-of-function mutations of FLG in the AD patients. The serine protease activity in the SC was increased not only in AD lesions but also in non-lesions of AD patients. We found, generally, that there was a positive correlation between the serine protease activity in the SC and the total serum immunoglobulin E (IgE) levels, serum thymus and activation-regulated chemokine (TARC) levels, and peripheral blood eosinophil counts. Moreover, the p.D386N or p.E420K in SPINK5 and FLG mutations were not significantly associated with the SC’s serine protease activity. Epidermal serine protease activity was increased even in non-lesions of AD patients. Such activity was found to correlate with a number of biomarkers of AD. Further investigations of serine proteases might provide new treatments and prophylaxis for AD.

scholarly journals Carbohydrate-controlled Serine Protease Inhibitor (Serpin) Production in Bifidobacterium Longum Subsp. Longum

2020 ◽  
Author(s):  
Stéphane Duboux ◽  
Mireille Golliard ◽  
Jeroen Muller ◽  
Gabriela Bergonzelli ◽  
Christoph Bolten ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Serine Protease ◽  
Serine Proteases ◽  
Intestinal Tract ◽  
Defense Mechanism ◽  
Inflammatory Diseases ◽  
Bifidobacterium Longum ◽  
Serine Protease Inhibitor ◽  
Innate Defense

Abstract The Serine Protease Inhibitor (serpin) protein has been suggested to play a key role in the interaction of bifidobacteria with the host. By inhibiting intestinal serine proteases, it might allow bifidobacteria to reside in specific gut niches. In inflammatory diseases where serine proteases contribute to the innate defense mechanism of the host, serpin may dampen the damaging effects of inflammation. In view of the beneficial roles of this protein, it is important to understand how its production is regulated. Here we demonstrate that B. longum NCC 2705 serpin production is tightly regulated by carbohydrates. Galactose and fructose increase the production of this protein while glucose prevents it, suggesting the involvement of catabolite repression. We identified that di- and oligosaccharides containing galactose (GOS) and fructose (FOS) moieties, including the human milk oligosaccharide Lacto-N-tetraose (LNT), are able to activate serpin production. Moreover, we show that the carbohydrate mediated regulation is conserved within B. longum subsp. longum strains but not in other bifidobacterial taxons harboring the serpin coding gene, highlighting that the serpin regulation circuits are not only species- but also subspecies- specific. Our work demonstrates that environmental conditions can modulate expression of an important effector molecule of B. longum, having potential important implications for probiotic manufacturing and supporting the postulated role of serpin in the ability of bifidobacteria to colonize the intestinal tract.

scholarly journals Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2

2021 ◽  
Vol 6 (1) ◽  
pp. 55-74
Author(s):  
Nurit P Azouz ◽  
Andrea Klingler ◽  
Victoria Callahan ◽  
Ivan Akhrymuk ◽  
Katarina Elez ◽  
...  
Keyword(s):  
Viral Load ◽  
Protease Inhibitor ◽  
Serine Protease ◽  
Inhibitory Activity ◽  
Serine Proteases ◽  
Serine Protease Inhibitor ◽  
Host Cells ◽  
S Protein ◽  
Relative Contribution ◽  
Alpha 1 Antitrypsin

Background: Host proteases have been suggested to be crucial for dissemination of MERS, SARS-CoV, and SARS-CoV-2 coronaviruses, but the relative contribution of membrane versus intracellular proteases remains controversial. Transmembrane serine protease 2 (TMPRSS2) is regarded as one of the main proteases implicated in the coronavirus S protein priming, an important step for binding of the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor before cell entry.  Methods: We developed a cell-based assay to identify TMPRSS2 inhibitors. Inhibitory activity was established in SARS-CoV-2 viral load systems. Results: We identified the human extracellular serine protease inhibitor (serpin) alpha 1 antitrypsin (A1AT) as a novel TMPRSS2 inhibitor. Structural modeling revealed that A1AT docked to an extracellular domain of TMPRSS2 in a conformation that is suitable for catalysis, resembling similar serine protease inhibitor complexes. Inhibitory activity of A1AT was established in a SARS-CoV-2 viral load system. Notably, plasma A1AT levels were associated with COVID-19 disease severity.  Conclusions: Our data support the key role of extracellular serine proteases in SARS CoV-2 infections and indicate that treatment with serpins, particularly the FDA-approved drug A1AT, may be effective in limiting SARS-CoV-2 dissemination by affecting the surface of the host cells.

Cartilage synthesizes the serine protease inhibitor PAI-1: Support for the involvement of serine proteases in cartilage remodeling

1991 ◽  
Vol 9 (3) ◽  
pp. 309-316 ◽  
Author(s):  
Benjamin V. Treadwell ◽  
Michele Pavia ◽  
Christine A. Towle ◽  
Vernon J. Cooley ◽  
Henry J. Mankin
Keyword(s):  
Protease Inhibitor ◽  
Serine Protease ◽  
Serine Proteases ◽  
Serine Protease Inhibitor ◽  
Pai 1

Inhibition of human kallikreins 5 and 7 by the serine protease inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI)

2005 ◽  
Vol 386 (11) ◽  
pp. 1173-1184 ◽  
Author(s):  
Norman M. Schechter ◽  
Eun-Jung Choi ◽  
Zhe-Mei Wang ◽  
Yasushi Hanakawa ◽  
John R. Stanley ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Serine Protease ◽  
Serine Proteases ◽  
Equilibrium Constants ◽  
Kinetic Studies ◽  
Serine Protease Inhibitor ◽  
Skin Development ◽  
Netherton Syndrome ◽  
Specific Association ◽  
20 Nm

Abstract LEKTI is a 120-kDa protein that plays an important role in skin development, as mutations affecting LEKTI synthesis underlie Netherton syndrome, an inherited skin disorder producing severe scaling. Its primary sequence indicates that the protein consists of 15 domains, all resembling a Kazal-type serine protease inhibitor. LEKTI and two serine proteases belonging to the human tissue kallikrein (hK) family (hK5 and hK7) are expressed in the granular layer of skin. In this study, we characterize the interaction of two recombinant LEKTI fragments containing three or four intact Kazal domains (domains 6–8 and 9–12) with recombinant rhK5, a trypsin-like protease, and recombinant rhK7, a chymotrypsin-like protease. Both fragments inhibited rhK5 similarly in binding and kinetic studies performed at pH 8.0, as well as pH 5.0, the pH of the stratum corneum where both LEKTI and proteases may function. Inhibition equilibrium constants (K i) measured either directly in concentration-dependent studies or calculated from measured association (k ass) and dissociation (k dis) rate constants were 1.2–5.5 nM at pH 8.0 and 10–20 nM at pH 5.0. At pH 8.0, k ass and k dis values were 4.7×105 M−1 s−1 and 5.5×10−4 s−1, and at pH 5.0 they were 4.0×104 M−1 s−1 and 4.3×10−4 s−1, respectively. The low K i and k dis values (t 1/2 of 20–25 min) indicate tight and specific association. Only fragment 6–9′ was a good inhibitor of rhK7, demonstrating a K i of 11 nM at pH 8.0 in a reaction that was rapidly reversible. These results show that LEKTI, at least in fragment form, is a potent inhibitor of rhK5 and that this protease may be a target of LEKTI in human skin.

In vivo contribution of serine proteases to the proteolytic activation of γENaC in aldosterone-infused rats

2012 ◽  
Vol 303 (7) ◽  
pp. F939-F943 ◽  
Author(s):  
Kohei Uchimura ◽  
Yutaka Kakizoe ◽  
Tomoaki Onoue ◽  
Manabu Hayata ◽  
Jun Morinaga ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Serine Protease ◽  
Serine Proteases ◽  
Serine Protease Inhibitor ◽  
Proteolytic Activation ◽  
New Strategy ◽  
Salt Sensitive Hypertension ◽  
Primary Cleavage

Aldosterone plays an important role in the regulation of blood pressure by modulating the activity of the epithelial sodium channel (ENaC) that consists of α-, β-, and γ-subunits. Aldosterone induces a molecular weight shift of γENaC from 85 to 70 kDa that is necessary for the channel activation. In vitro experiments demonstrated that a dual cleavage mechanism is responsible for this shift. It has been postulated that furin executes the primary cleavage in the Golgi and that the second cleavage is provided by other serine proteases such as prostasin or plasmin at the plasma membrane. However, the in vivo contribution of serine proteases to this cleavage remains unclear. To address this issue, we administered the synthetic serine protease inhibitor camostat mesilate (CM) to aldosterone-infused rats. CM decreased the abundance of the 70-kDa form of ENaC and led to a new 75-kDa form with a concomitant increase in the urinary Na-to-K ratio. Because CM inhibits the protease activity of serine proteases such as prostasin and plasmin, but not furin, our findings strongly indicate that CM inhibited the second cleavage of γENaC and subsequently suppressed ENaC activity. The results of our current studies also suggest the possibility that the synthetic serine protease inhibitor CM might represent a new strategy for the treatment of salt-sensitive hypertension in humans.

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