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Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants

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Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants International Journal of Molecular Sciences Review Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants Gilles Lalmanach 1,2,* , Ahlame Saidi 1,2 , Paul Bigot 1,2, Thibault Chazeirat 1,2, Fabien Lecaille 1,2 and Mylène Wartenberg 1,2 1 Université de Tours, 37000 Tours, France; [email protected] (A.S.); [email protected] (P.B.); [email protected] (T.C.); [email protected] (F.L.); [email protected] (M.W.) 2 INSERM, UMR1100, Centre d’Etude des Pathologies Respiratoires, 37000 Tours, France * Correspondence: [email protected]; Tel.: +33-2-47-36-61-51 Received: 20 February 2020; Accepted: 10 March 2020; Published: 12 March 2020 Abstract: Besides their primary involvement in the recycling and degradation of proteins in endo-lysosomal compartments and also in specialized biological functions, cysteine cathepsins are pivotal proteolytic contributors of various deleterious diseases. While the molecular mechanisms of regulation via their natural inhibitors have been exhaustively studied, less is currently known about how their enzymatic activity is modulated during the redox imbalance associated with oxidative stress and their exposure resistance to oxidants. More specifically, there is only patchy information on the regulation of lung cysteine cathepsins, while the respiratory system is directly exposed to countless exogenous oxidants contained in dust, tobacco, combustion fumes, and industrial or domestic particles. Papain-like enzymes (clan CA, family C1, subfamily C1A) encompass a conserved catalytic thiolate-imidazolium pair (Cys25-His159) in their active site. Although the sulfhydryl group (with a low acidic pKa) is a potent nucleophile highly susceptible to chemical modifications, some cysteine cathepsins reveal an unanticipated resistance to oxidative stress. Besides an introductory chapter and peculiar attention to lung cysteine cathepsins, the purpose of this review is to afford a concise update of the current knowledge on molecular mechanisms associated with the regulation of cysteine cathepsins by redox balance and by oxidants (e.g., Michael acceptors, reactive oxygen, and nitrogen species). Keywords: cathepsin; chronic obstructive pulmonary disease (COPD); cysteine; cysteine protease; lung inflammation; oxidation; proteolysis; thiol 1. Cysteine Cathepsins Proteases are classified into six distinct types according to residues essential for their enzymatic activity and their catalytic mechanism: serine proteases, acid (aspartate and glutamate) proteases, cysteine proteases, metalloproteases, and threonine proteases [1,2]. Cysteine proteases are widely expressed in animals, plants, fungi, parasites, bacteria or viruses [3,4]. Among them, cysteine cathepsins B, C, F, H, K, L, O, S, V, W and X (clan CA, family C1, subfamily C1A) are structurally related to papain (from Carica papaya)[5,6]. Primarily, cysteine cathepsins are ubiquitous lysosomal proteases that are active at acidic pH and are rapidly inactivated at neutral pH (except cathepsin S, CatS) [7]. In addition, some cathepsins (e.g., cathepsins B, L, K, H and S) could be secreted into the extracellular medium by alveolar macrophages, epithelial cells, pneumocytes or fibroblasts [8,9]. Alternatively, under specific pathophysiological conditions, truncated cathepsins could be targeted to mitochondria or found in the cytosol before being imported into the nuclear compartment, where they can even function as active proteases [10,11]. This unexpected cellular roadmap was nicely Int. J. Mol. Sci. 2020, 21, 1944; doi:10.3390/ijms21061944 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 1944 2 of 20 summarizedInt. J. Mol. Sci. elsewhere2020, 21, 1944 [12]. The half-life of cysteine cathepsins may vary from a few minutes2 of 20 to several hours depending on the cellular environment [13,14]. Besides housekeeping recycling and degradationsummarized of proteinselsewhere within [12]. The acidic half compartments,-life of cysteinethey cathepsins participate may invary specific from biologicala few minutes processes, to suchseveral as the hours maturation depending of some on the prohormones, cellular environment apoptosis, [13,14]. antigen Besides presentation housekeeping or remodeling recycling and of the extracellulardegradation matrix of proteins and basementwithin acidic membrane compartments, [15]. They they areparticipate also involved in specific in pathologicalbiological processes, processes (e.g.,such rheumatoid as the maturation arthritis, of some osteoporosis, prohormones, asthma, apoptosis, cancer, antigen and inflammation). presentation or remodeling Accordingly, of the some cysteineextracellular cathepsins matrix are and considered basement membrane as valuable [15]. therapeutic They are also targets, involved and pharmacologicalin pathological processes inhibitors (e.g., rheumatoid arthritis, osteoporosis, asthma, cancer, and inflammation). Accordingly, some of these proteases are currently in clinical trials [16–19]. Cysteine cathepsins are synthesized as cysteine cathepsins are considered as valuable therapeutic targets, and pharmacological inhibitors of pre-proenzymes, and their corresponding proregions participate in folding and enzyme stability these proteases are currently in clinical trials [16–19]. Cysteine cathepsins are synthesized as pre- (for review: Reference [6]). The processing of the mature active form occurs by cleavage and release proenzymes, and their corresponding proregions participate in folding and enzyme stability (for of thereview: propeptide. Reference Propeptides[6]). The processing may also of the act mature as competitive active form inhibitors occurs by of cleavage their parent and release mature of and activethe propeptide. enzyme (catalytic Propeptides domain). may Inalso addition, act as competitive cysteine cathepsins inhibitors canof their be transcriptionally parent mature and modulated active as wellenzyme regulated (catalytic by domain). pH, temperature, In addition, oxidation, cysteine cath glycosaminoglycansepsins can be transcriptionally (GAGs) and modulated by endogenous as inhibitorswell regulated [17], including by pH, thetemperature, cystatin family oxidation, (i.e., stefins,glycosaminoglycans cystatins, and (GAGs) kininogens) and [by3,20 endogenous,21]. Cysteine cathepsinsinhibitors are [17], monomeric including the enzymes cystatin (22–28 family kDa (i.e., range),stefins, cystatins, with the exceptionand kininogens) of cathepsin [3,20,21]. C, Cysteine whichis a tetramericcathepsin molecules are monomeric (circa 200 enzymes kDa) [(2222].–28 The kDa archetypal range), with structural the exception shape of of cathepsin cathepsins C, which corresponds is a to atetrameric left (L) domain molecule and (circa a right200 kDa) (R) domain[22]. The thatarchetypal are of structural similar size. shape Both of cathepsins CatB and corresponds CatX share an additionalto a left (L) structure domain called and a the right occlusion (R) domain loop that that are drives of similar their siz exopeptidasee. Both CatB activityand CatX [23 share,24]. an Their catalyticadditional mechanism structure requires called the the occlusion presence loop of a catalyticthat drives dyad their composed exopeptidase of Cys25 activity (papain [23,24]. numbering; Their subsequentlycatalytic mechanism used throughout requires the the presence text to designateof a catalytic the dyad catalytic composed cysteine of Cys25 within (papain the active numbering; site) and subsequently used throughout the text to designate the catalytic cysteine within the active site) and + His159. At pH 3.5–8.0, this dyad is under its ionic form, i.e., thiolate/imidazolium (Cys-S−/His-ImH ), − + whichHis159. results At pH from 3.5– the8.0, transfer this dyad of is a under proton its from ionic Cysform, to i.e., His. thiolate/ A thirdimidazolium residue (Asn175) (Cys-S / contributesHis-ImH ), to which results from the transfer of a proton from Cys to His. A third residue (Asn175) contributes to the catalytic mechanism by maintaining His159 via a hydrogen bond in the correct positioning [25]. the catalytic mechanism by maintaining His159 via a hydrogen bond in the correct positioning [25]. The first step of the mechanism is a nucleophilic attack of the carbonyl group of the peptide bond by the The first step of the mechanism is a nucleophilic attack of the carbonyl group of the peptide bond by thiolate group. It results in an anionic tetrahedral intermediate that forms an oxyanion, stabilized by a the thiolate group. It results in an anionic tetrahedral intermediate that forms an oxyanion, stabilized hydrogenby a hydrogen bond between bond between Cys25 Cys25 and Gln19. and Gln19. Then, Then, His159 His159 loses loses its proton, its proton, leading leading to the to the release release of the amineof the portion amine of portion the substrate of the substrate and the subsequentand the subsequent contribution contribution of a water of a molecule water molecule to the formation to the of aformation second intermediateof a second intermediate acyl-enzyme. acyl- Theenzyme. ending The deacylationending deacylation step allows step allows both both the releasethe release of the carboxylof the carboxyl portion portion of the hydrolyzed of the hydrolyzed substrate substrate and recovery and recovery of the of free the free enzyme enzyme [25 ,[25,26]26] (Figure (Figure1).1). FigureFigure 1. 1.The The hydrolysis hydrolysis mechanism mechanism viavia cysteinecysteine cathepsins. (A (A) )Catalytic
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