Review article: Medical intelligence | Published 20 July 2010, doi:10.4414/smw.2010.13042 Cite this as: Swiss Med Wkly. 2010;140:w13042 Cathepsins and their involvement in immune responses Sébastien Conus, Hans-Uwe Simon Institute of Pharmacology, University of Bern, Bern, Switzerland Correspondence to: cleaving proteases (= caspases) which cleave a wide range Sébastien Conus Ph.D. of cellular substrates [5]. Institute of Pharmacology Besides caspases, cathepsins have recently been shown University of Bern to be associated with cell death regulation [6–12] and vari- Friedbühlstrasse 49 3010 Bern ous other physiological and pathological processes, such as Switzerland maturation of the MHC class II complex, bone remodel- [email protected] ling, keratinocyte differentiation, tumour progression and metastasis, rheumatoid arthritis and osteoarthritis, as well Summary as atherosclerosis [13, 14] (table 1). Thus, cathepsins ap- pear to play a significant role in immune responses. In this The immune system is composed of an enormous variety of review we discuss recent advances addressing the role of cells and molecules that generate a collective and coordin- lysosomal proteases in the diverse aspects of the immune ated response on exposure to foreign antigens, called the response, and also the involvement of cathepsins in the immune response. Within the immune response, endo-lyso- pathogenesis of diseases in which these proteases seem not somal proteases play a key role. In this review we cover to be properly under control. specific roles of cathepsins in innate and adaptive immu- nity, as well as their implication in the pathogenesis of sev- The cathepsin family eral diseases. Lysosomes are membrane-bound organelles which repres- Key words: adaptive and innate immunity; apoptosis; ent the main degradative compartment in eukaryotic cells. cathepsin; immune response; lysosome Some cell types, mainly derived from the haematopoietic lineage, contain a specialised lysosomal compartment Introduction which can secrete its content into the extracellular envir- onment in response to external stimuli [15]. These organ- Innate and adaptive immune responses are components of elles have been commonly named “secretory lysosomes” a defence mechanism which has become increasingly spe- or “lysosomal-related organelles” and include lytic gran- cialised with evolution. This immune system is able to gen- ules, major histocompatibility (MHC) class II compart- erate numerous cells and molecules capable of specifically ments, and basophil and azurophil granules [16]. Conven- recognising and eliminating an apparently unlimited vari- tional and secretory lysosomes share similar proprieties, ety of foreign invaders by functioning cooperatively [1]. such as the internal acidic pH and presence of degradative At inflammatory sites, accumulation of these specialised proteins. However, secretory lysosomes are distinguished cells and molecules helps to remove invading agents effi- from conventional lysosomes by their ability to undergo ciently, but may also amplify the inflammatory response by regulated secretion [17]. damaging surrounding tissue [2]. Therefore, and in particu- Lysosomes contain a considerable number of proteases. lar under inflammatory conditions during which stimulated Among them the best known are the cathepsins. The cells are releasing toxic mediators, the numbers of inflam- cathepsin family contains chiefly cysteine (Cys) proteases, matory cells must be tightly controlled. although cathepsins A and G are serine proteases and To eliminate unwanted and potentially harmful cells cathepsins D and E are aspartic proteases. In humans el- from inflamed tissues without releasing hazardous intracel- even cysteine cathepsins are known: cathepsins B, C (J, lular contents, apoptosis, a crucial physiological form of dipeptidyl peptidase I or DPPI), F, H, K (O2), L, O, S, V programmed cell death, is conducted [3, 4]. The central (L2), X (P,Y,Z) and W (lymphopain) [18, 19]. They are all component of apoptosis is a proteolytic amplifying cascade members of the papain family, which belongs to the clan involving specialised proteases called cysteinyl-aspartate- CA (cathepsins) of cysteine proteases. The clan CA con- Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 1 of 8 Review article: Medical intelligence Swiss Med Wkly. 2010;140:w13042 tains all the families of peptidases known to have structures rheumatoid arthritis (RA), and osteoarthritis [14, 18, 21] similar to that of papain [20]. (table 1). The role of cathepsins in apoptosis was dis- To prevent any uncontrolled proteolytic activity, covered quite recently [25, 26]. For their proapoptotic cathepsins are kept tightly in check. All cathepsins are syn- function, cathepsins must be released from the lysosome thesised as inactive zymogens. The processing of the inact- into the cytosol by either lysosomal destabilisation [27] ive zymogen into a catalytically active enzyme usually oc- or lysosomal membrane permeabilisation (LMP) [28]. So curs within the lysosome by other active proteases or by far a number of molecules have been found to target the autocatalysis under certain specific conditions, such as low lysosomal membrane and induce apoptosis in a caspase-de- pH or the presence of glycosaminoglycans [21]. The major pendent or -independent manner (reviewed in [1]). regulators of cathepsin activity are endogenous protein in- hibitors known as cystatins, stefins, thyropins, and serpins Cathepsins and innate immunity which bind tightly to the target enzyme, thereby prevent- ing substrate hydrolysis [22]. At least for some cathepsins, Lysosome-mediated apoptosis activity can also be lost by degradation or by oxidation of Cathepsins have been shown to play significant roles in the the Cys residue in the catalytically active site [6]. physiological process of apoptosis. Moreover, the resolu- Cathepsins cleave their substrate in a relatively unspe- tion of inflammation depends on apoptosis of inflammat- cific manner. While cathepsins B and H function as ex- ory cells (e.g. neutrophils and eosinophils) and their subse- opeptidases and endopeptidases, cathepsins D, E, F, G, K, quent clearance by phagocytes such as macrophages. Thus L, S and V are endopeptidases, and cathepsins A, C and it is very likely that cathepsins are involved in innate im- X are exopeptidases. Following synthesis, cathepsins are mune responses. glycosylated posttranslationally and transported to lyso- Indeed, cathepsin D has been shown to be a key molec- somes via the mannose-6-phosphate receptor pathway, ule of neutrophil apoptosis by directly activating the initiat- where their concentration can reach up to 1 mM [23]. or caspase-8 [29] (fig. 1A). Interestingly, this newly identi- Depending on the tissue, a number of cathepsins show sig- fied pathway in neutrophils is blocked during inflammatory nificant differences in protein expression levels and ratios, conditions and is crucial for the resolution of innate im- suggesting that individual cathepsins may have highly spe- mune responses, as demonstrated by the observation that cific cellular functions [24]. delayed neutrophil apoptosis due to cathepsin D deficiency Besides their main function in lysosomal protein re- amplifies and prolongs neutrophilic inflammation in vivo. cycling, cathepsins play significant roles in a variety of Moreover, cathepsin B has also been shown to be involved physiological processes such as Ag processing, wound in apoptosis of immune cells. Blomgran et al. reported that, healing, bone remodelling, prohormone and proenzyme ac- during microbe-induced apoptosis of human neutrophils, tivation, hair cycle, reproduction and also in diseases such ROS-dependent release of cathepsin B into cytosol induces as cancer, bronchial asthma, atherosclerosis, periodontitis, cleavage of the pro-apoptotic Bcl-2 family member Bid, Table 1 Cathepsins and their functions in the immune system. Cathepsin Class Distribution Function Involvement in disease Cathepsin B Cysteine Ubiquitous Early neutrophil, T and B cell apoptosis Inflammatory disorders TLRs signalling and TNF-alpha production Alzheimer’s disease Selectors for peptide-MHC II complexes Cancer Cathepsin C Cysteine Ubiquitous Activation of granzymes A and B Inflammatory disorders Cathepsin D Aspartic Ubiquitous Early neutrophil, T and B cell apoptosis Inflammatory disorders, cancer Selectors for peptide-MHC II complexes Rheumatoid arthritis, Alzheimer’s disease ECM degradation Cathepsin E Aspartic Immune cells Selectors for peptide-MHC II complexes Atopic dermatitis, dermatitis Cathepsin F Cysteine Ubiquitous TLRs signalling Cancer Cathepsin G Serine Neutrophil lysosomes IL-8, IL-1beta and TNF-alpha activation Inflammatory disorders Human B cells (exogenous source) IL-6 disactivation Destruction of the autoantigen MBP (in B cells) Cathepsin H Cysteine Ubiquitous ECM degradation Cancer Cathepsin K Cysteine DCs, epithelial cells TLRs signalling Rheumatoid arthritis ECM degradation and bone remodeling Cathepsin L Cysteine Ubiquitous TLRs signalling Thymic pathology Selectors for peptide-MHC II complexes Atherosclerosis NKT and CD4 T cells production, Rheumatoid arthritis neuronal cell death and osteoclastic bone degradation Cancer ECM degradation Cathepsin S Cysteine APC TLRs signalling Arthritis, atherosclerosis Selectors for peptide-MHC II complexes Bronchial asthma, COPD NKT cells production, ECM degradation Psoriasis, cancer Cathepsin V Cysteine Ubiquitous Selectors for peptide-MHC II complexes,