cells Review Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy 1 2, 1, , Valeria De Pasquale , Anna Moles y and Luigi Michele Pavone * y 1 Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; [email protected] 2 Institute of Biomedical Research of Barcelona, Spanish Research Council, 08036 Barcelona, Spain; [email protected] * Correspondence: [email protected]; Tel.: +39-081-7463043 These authors contributed equally to this work. y Received: 25 March 2020; Accepted: 14 April 2020; Published: 15 April 2020 Abstract: Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases. Keywords: cathepsins; mucopolysaccharidoses; lysosomal storage diseases; therapy 1. Introduction Cathepsins (CTSs) are a family of proteases expressed in all living organisms. In humans, CTSs comprise 15 proteolytic enzymes that are classified in three distinct groups based on the key amino acid within their active site, namely serine (CTS A and G), cysteine (CTS B, C, H, F, L, K, O, S, V, X, W), and aspartate (CTS D and E) [1]. These proteases, which mostly require mild acidic conditions for their optimal activity, are all synthesized as proenzymes. Although CTSs are mainly localized in the lysosomes where the acidic environment facilitates their proteolytic activity, they are also found in the cytoplasm, nucleus, and extracellular space where they participate in extracellular matrix (ECM) protein degradation, cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles (Figure1)[ 2–7]. While some CTSs are ubiquitously expressed in the whole body, some are expressed in a more restricted pattern, suggesting specific cellular functions for distinct CTSs. Cells 2020, 9, 979; doi:10.3390/cells9040979 www.mdpi.com/journal/cells Cells 2020, 9, 979 2 of 22 Cells 2020, 9, x 2 of 21 FigureFigure 1. 1.Cellular Cellular localization localization of of cathepsins cathepsins (CTSs). (CTSs). Here,Here, wewe provideprovide somesome examples of CTS functions functions in inthe the different different locations. locations. CTSs CTSs in in the the extracellular extracellular space space can can cleave cleave extracellular extracellular matrix matrix proteins, proteins, cell cellreceptors receptors,, or orcytokines cytokines [2] [. 2CTSs]. CTSs can can also also be befound found in caveolae in caveolae triggering triggering cell- cell-surfacesurface proteolytic proteolytic events eventsassociated associated with withcell migration cell migration [3], or [3 ],in orthe in endolysosomal the endolysosomal [4] and [4] andautolysosomal autolysosomal compartments compartments where wherethey theyprocess process the compartment’s the compartment’s cargo cargo[5]. CTSs [5]. in CTSs the nuclei in the play nuclei an playimportant an important role in cell role cycle in cell regulation cycle regulation[6], while [ 6in], the while cytosol in the mediate cytosol mitochondrial mediate mitochondrial permeabilization permeabilization and apoptosis and through apoptosis cleavage through of Bid cleavageand release of Bid of and Bax release [7]. Some of Bax of the [7]. cellular Some of components the cellular componentsdisplayed in displayedthe figure inhave the been figure adapted have been from adaptedSmart Servier from Smart Medical Servier Art under Medical Creative Art under Commons Creative Attribution Commons 3.0 AttributionUnported License. 3.0 Unported License. CTSsCTSs have have been been shown shown toto playplay essentialessential roles in coagulation, digestion, digestion, hormone hormone liberation, liberation, adipogenesis,adipogenesis, peptide peptide synthesis, synthesis, immuneimmune response,response, and many many other other vital vital processes processes [1,8 [1,].8 ].Abnormal Abnormal expressionexpression and and/or/or activity activity of of CTSs CTSs have have beenbeen associatedassociated with with a a variety variety o off human human diseases, diseases, including including inflammatoryinflammatory and and cardiovascular cardiovascular diseases,diseases, neurodegenerative disorders, disorders, diabetes, diabetes, obesity, obesity, cancer, cancer, kidneykidney dysfunction, dysfunction, and and many many others others (Table(Table1 ).1). TableTable 1.1. Cathepsin-relatedCathepsin-related diseases. diseases. Cathepsin MEROPS Type Disease References Cathepsin(CTS) (CTS) Type MEROPSID [9] ID [9] Disease References CardiovascularCardiovascular disease disease[10,11] [10,11] CharcotCharcot-Marie-Marie Tooth diseases Tooth diseases[12] [12] CTSACTSA Serine Serine S10.002 S10.002 GalactosialidosisGalactosialidosis [13] [13] MuscularMuscular dystrophy dystrophy [14] [14] Alzheimer’s disease [15] CancerAlzheimer’s disease[16] [15] CTSB Cysteine C01.060 Cardiovascular diseaseCancer [17–19] [16] CTSB Cysteine C01.060 LiverCardiovascular fibrosis disease[20,21] [17–19] PancreatitisLiver fibrosis[22,23] [20,21] CancerPancreatitis [24,25] [22,23] CTSC Cysteine C01.070 Inflammatory/autoimmune diseases [26–28] Papillon–Lefèvre syndromeCancer [29] [24,25] CTSC Cysteine C01.070 AcuteInflammatory and chronic renal/autoimmune disease diseases[30–32] [26–28] Papillon–LefCancer èvre syndrome[33–35] [29] Cardiac disease [36] Acute and chronic renal disease [30–32] Chronic obstructive pulmonary disease [37] Gaucher diseaseCancer [38] [33–35] CTSD Aspartate A01.009 Liver fibrosisCardiac disease[21] [36] NeurodegenerativeChronic obstructive disorders pulmonary disease[39–41] [37] Gaucher disease [38] CTSD Aspartate A01.009 Neuronal ceroid lipofuscinosis 10 [42,43] Niemann-PickLiver type fibrosisC [44] [21] NeurodegenerativePancreatitis disorders[23] [39–41] Chronic obstructiveNeuronal pulmonary ceroid lipofuscinosis disease 10[37,45] [42,43] CTSE Aspartate A01.010 NeuropathiesNiemann-Pick type C[46,47] [44] Pancreatic cancerPancreatitis [48] [23] Cells 2020, 9, 979 3 of 22 Table 1. Cont. Cathepsin (CTS) Type MEROPS ID [9] Disease References Chronic obstructive pulmonary disease [37,45] CTSE Aspartate A01.010 Neuropathies [46,47] Pancreatic cancer [48] Alzheimer’s disease [49] CTSF Cysteine C01.018 Cancer [50] Neuronal ceroid lipofuscinosis 13 [43,51] Autoimmune diseases [52,53] Cystic fibrosis [54] Chronic obstructive pulmonary disease [37,55] Coronary artery disease [56] CTSG Serine S01.133 Inflammatory bowel disease [57] Pancreatitis [58] Psoriasis [59] Rheumatoid arthritis [60] Aortic aneurism [61,62] Myopia [43,63] CTSH Cysteine C01.040 Narcolepsy [64] Type I diabetes [65] Aortic aneurism [61,62] Atherosclerosis [66] Cancer [67] CTSK Cysteine C01.036 Chronic obstructive pulmonary disease [37] Lung fibrosis [68] Osteoarthritis; Osteoporosis [69–73] Pycnodysostosis [43,73] Cancer [74,75] CTSL Cysteine C01.032 [19,61,62, Cardiovascular disease 76] Chronic kidney disease; Diabetic [77,78] nephropathy CTSO Cysteine C01.035 Unknown Alzheimer’s disease [79] [18,19,80, Atherosclerosis 81] CTSS Cysteine C01.034 Cancer [82] Chronic obstructive pulmonary disease [37] Chronic kidney disease [83,84] Gaucher disease [38] Metabolic syndromes [85] Atherosclerosis [81,86] Cancer [87–89] CTSV Cysteine C01.009 Hyperhomocysteinemia [90] Myasthenia gravis [91] Sickle cell disease [92] Gastritis [93,94] CTSW Cysteine C01.037 Leukaemia [95] Ageing and neurodegeneration [96] CTSX/Z Cysteine C01.013 Cancer [88,97–99] Helicobacter pylori [14,100] The activity and stability of CTSs are tightly regulated by glycosaminoglycans (GAGs), a class of linear, negatively charged polysaccharides that comprise the non-sulfated hyaluronic acid (HA) Cells 2020, 9, 979 4 of 22 and the sulfated chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), heparin and heparan sulfate (HS). The protease–GAG interactions may enable autocatalytic activation of CTSs, promote conformational changes in the CTS structures that may increase their affinity for the substrate, thus enhancing their biological activity, and finally, protect proteases from alkaline pH-induced inactivation [101–103]. Most of the GAGs are covalently attached to a core protein, forming proteoglycans that are abundantly found at the cell surface and ECM [104,105]. Accumulation of undigested GAGs occurs in the lysosomes as well as on the cell surface and ECM in patients affected by Mucopolysaccharidoses