Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants

Lalmanach, Gilles; Saidi, Ahlame; Bigot, Paul; Chazeirat, Thibault; Lecaille, Fabien; Wartenberg, Mylène

doi:10.3390/ijms21061944

Cited by 26 publications

(19 citation statements)

References 179 publications

(210 reference statements)

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“…These opposing effects of reducing and oxidizing agents on CTSS and its endogenous inhibitor cystatin C highlight the complex interplay involved in maintaining proteolytic homeostasis. Interestingly, CTSS is less susceptible to oxidative stress induced by H 2 O 2 in acidic pH conditions compared to other cysteine cathepsins [193]. The microbiome has also been shown to directly regulate CTSS activity via the production of small molecule dipeptide aldehydes that target the catalytic cysteines, blocking the active site of CTSS and preventing binding of substrates [194].…”

Section: Regulation Of Activitymentioning

confidence: 99%

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

et al. 2020

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Dysregulated expression and activity of cathepsin S (CTSS), a lysosomal protease and a member of the cysteine cathepsin protease family, is linked to the pathogenesis of multiple diseases, including a number of conditions affecting the lungs. Extracellular CTSS has potent elastase activity and by processing cytokines and host defense proteins, it also plays a role in the regulation of inflammation. CTSS has also been linked to G-coupled protein receptor activation and possesses an important intracellular role in major histocompatibility complex class II antigen presentation. Modulated CTSS activity is also associated with pulmonary disease comorbidities, such as cancer, cardiovascular disease, and diabetes. CTSS is expressed in a wide variety of immune cells and is biologically active at neutral pH. Herein, we review the significance of CTSS signaling in pulmonary diseases and associated comorbidities. We also discuss CTSS as a plausible therapeutic target and describe recent and current clinical trials examining CTSS inhibition as a means for treatment. Proteases in pulmonary diseases Research in the last 60 years has demonstrated that proteases are critical contributors to pulmonary disease pathophysiology. Initially known as protein-degrading enzymes with a restricted spectrum of substrates, recent studies have revealed that the diversity of protease substrates and biological effects triggered by their processing is vast [1, 2]. Proteases are primarily known for their matrix degradation capabilities, but also play significant roles in other biological mechanisms such as angiogenesis, growth factor bioavailability, cytokine processing, receptor shedding and activation, as well as cellular processes including migration, proliferation, invasion, and survival [3]. Importantly, protease activity requires tight regulation, and disruption of the close interplay between proteases, substrates and inhibitors may contribute to the pathogenesis and progression of a variety of pulmonary diseases, including muco-inflammatory diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), as well as infection [4]. In pulmonary diseases with a high neutrophil burden such as CF, a protease:antiprotease imbalance is frequently observed. The activity of proteases such as neutrophil elastase (NE) in the respiratory tract is regulated by antiproteases, such as α1-antitrypsin (A1AT) [5], secretory leukoprotease inhibitor (SLPI) [6] and elafin [7]. However, in diseases like CF, the antiproteases are overburdened by their cognate proteases and this imbalance can result in chronic airway inflammation, decreased mucociliary clearance, mucus obstruction, extracellular matrix (ECM) remodeling, increased susceptibility to infection and impaired immune responses [8].

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Section: Regulation Of Activitymentioning

confidence: 99%

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

et al. 2020

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“…The pKa of cysteine residues is greatly influenced by the chemical environment, including the proximity of charged residues or hydrogen bonding 52 . Cysteines with particularly low pKa values have been reported at the active sites of the thioredoxin superfamily 54 or of cysteine proteases 55 . However, the current available vimentin structures do not provide a complete view of the environment surrounding the lateral chain of Cys328 to discern the cause of the low pKa values detected.…”

Section: Resultsmentioning

confidence: 99%

Elucidating vimentin interaction with zinc ions and its interplay with oxidative modifications through crosslinking assays and molecular dynamics simulations

Mónico

Guzmán-Caldentey

et al. 2021

Preprint

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The intermediate filament protein vimentin is involved in essential cellular processes, including cell division and stress responses. Vimentin oxidative modifications impact network reorganization and its single cysteine residue, Cys328, acts as a redox sensor. Vimentin binds zinc, which influences its assembly by undefined mechanisms. Here, results from combined biochemical and molecular dynamics studies support that zinc ions interact with Cys328 in its thiolate form, whereas Glu329 and Asp331 stabilize zinc coordination. Vimentin oxidation can induce disulfide crosslinking, implying a close proximity of cysteine residues in certain vimentin associations, validated by our computational models. Notably, micromolar zinc concentrations selectively prevent Cys328 alkylation and crosslinking. These effects are not mimicked by magnesium, consistent with the fewer magnesium ions hosted at the cysteine region. Altogether, our results pinpoint the region surrounding Cys328, highly conserved in type III intermediate filaments, as a hot spot for zinc binding, which modulates Cys328 reactivity and vimentin assembly.

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“…[59]. The mechanisms that lead to oxidants inhibiting CPs have recently been examined [60]. For example, inhibition of papain by H2O2 results from the formation of sulfenic acid which reacts with adjacent free thiol to form mixed disulfides.…”

Section: Ehistolytica Cp Activity Is Impaired By Lacidophilusmentioning

confidence: 99%

Insights Into the Mechanisms of <em>Lactobacillus acidophilus</em> Activity Against <em>Entamoeba histolytica</em> by Using Thiol-Redox-Proteomics

Sarid¹,

Zanditenas²,

Ye³

et al. 2022

Preprint

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Amebiasis is an intestinal disease transmitted by the protist parasite, Entamoeba histolytica. Lactobacillus acidophilus is a common inhabitant of healthy human gut and a probiotic that has antimicrobial properties against a number of pathogenic bacteria, fungi, and parasites. The aim of this study was to investigate the amebicide activity of L. acidophilus and its mechanisms. For this purpose E.histolytica and L.acidophilus were co-incubated and the parasite’s viability was determined by eosin dye exclusion. The level of ozidized proteins (OXs) in the parasite was determined by resin-assisted capture RAC (OX-RAC). Incubation with L.acidophilus for two hours reduced the viability of E.histolytica trophozoites by 50%. As a result of the interaction with catalase, an enzyme that degrades hydrogen peroxide (H2O2) to water and oxygen, this amebicide activity is lost, indicating that it is mediated by H2O2 produced by L.acidophilus. Redox proteomics shows that L. acidophilus triggers the oxidation of many essential amebic enzymes like pyruvate:ferredoxin oxidoreductase, the lectin Gal/GalNAc and cysteine proteases (CPs). Further, trophozoites of E.histolytica incubated with L.acidophilus show reduced binding to mammalian cells. These results support L.acidophilus as a prophylactic candidate against amebiasis.

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Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants

Cited by 26 publications

References 179 publications

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

Elucidating vimentin interaction with zinc ions and its interplay with oxidative modifications through crosslinking assays and molecular dynamics simulations

Insights Into the Mechanisms of <em>Lactobacillus acidophilus</em> Activity Against <em>Entamoeba histolytica</em> by Using Thiol-Redox-Proteomics

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