Mature Cathepsin L Is Substantially Active in the Ionic Milieu of the Extracellular Medium

Dehrmann, Frieda; Coetzer, Theresa H.T.; Pike, Robert N.; Dennison, Christopher

doi:10.1006/abbi.1995.9924

Cited by 57 publications

(43 citation statements)

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“…Nonetheless, there is clear evidence that some activity persists most likely against a limited range of substrates [87][88][89]. Identification of the relevant physiological targets of cytosolic cathepsins has been complicated by the fact that many apoptotic signalling cascades occur in parallel.…”

Section: Lysosomal-mediated Apoptosismentioning

confidence: 99%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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The innate and adaptive immune system utilise endocytic protease activity to promote functional immune responses. Cysteine and aspartic proteases (cathepsins) constitute a subset of endocytic proteases, the immune function of which has been described extensively. Although historically these studies have focused on their role in processes such as antigen presentation and zymogen processing within the endocytic compartment, recent discoveries have demonstrated a critical role for these proteases in other intracellular compartments, and within the extracellular milieu. It has also become clear that their pattern of expression and substrate specificities are more diverse than was first envisaged. Here, we discuss recent advances addressing the role of lysosomal proteases in various aspects of the immune response. We pay attention to reports demonstrating cathepsin activity outside of its canonical endosome/lysosome microenvironment.Key words: Cathepsins . Endosomes . Immune regulation . Lysosomes IntroductionThe endosome/lysosome compartments, together with the cytosolic proteasomes, are the two major protein degradation systems in cells. Both have emerged as having many important regulatory functions in addition to their role in protein breakdown for amino acid recycling. For example, limited proteolysis within the endocytic pathway can induce activating conformational changes [1,2], release functional proteins from chaperones [3], and cleave soluble bioactive molecules from membrane-anchored precursors [4]. The concept of ''regulation through limited destruction'' is evident in many processes in innate and adaptive immunity. Endosome/lysosome-located proteases play key roles in antigen processing and presentation, cytokine regulation, NKT cell development, activation of serine protease zymogens in regulated secretory granules, integrin activation, induction of apoptosis and TLR signalling. Given that these processes may also be associated with undesirable immune responses and inflammation, the proteases involved may be considered as attractive drug targets. EnzymesEndosomes and lysosomes harbour mainly cysteine and aspartic acid proteases so-named because their active site utilises either a cysteine thiol or an aspartic acid as a key part of the catalytic site. Some endosome/lysosome located serine proteases such as cathepsin G, granzymes and thymus specific serine protease (TSSP) have important roles in the immune system; however, we focus primarily here on the cysteine and aspartic proteases. Most of the lysosomal cysteine proteases are related to papain and belong to the so-called C1 family. These include cathepsins L, S, C, F, H, B, X, K, V and W. Cathepsins D and E are also found in lysosomes but are aspartic acid proteases related to pepsin. An additional cysteine protease is found in lysosomes, which is more closely related to the caspases. This is asparaginyl endopeptidase (AEP) or legumain, a member of the C13 family. Some of these enzymes are endopeptidases (cathepsins S, L, K, F, V, D, E and AEP), where...

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Section: Lysosomal-mediated Apoptosismentioning

confidence: 99%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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“…Most tissues of the joint are composed primarily of ECM and key roles in the degeneration of this are performed by proteases active at neutral pH (serine and metallo proteases). However some proteases with an acidic pH optimum have been shown to be active at neutral pH under some circumstances (Almeida et al, 2001;Berardi et al, 2001;Brix, Lemansky, & Herzog, 1996;Buck, Karustis, Day, Honn, & Sloane, 1992;Buttle et al, 1991;Dehrmann, Coetzer, Pike, & Dennison, 1995) and there is no doubt that the activity of cathepsin K in the acidic lacunae of osteoclasts is crucial to the turnover of the organic matrix of long bone. MMP collagenases are likely to play a prominent role in the cleavage of cartilage collagens.…”

Section: Discussionmentioning

confidence: 99%

The role of proteases in pathologies of the synovial joint

Jones¹,

Riley²,

Buttle³

2008

The International Journal of Biochemistry & Cell Biology

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Synovial (diarthrodial) joints are employed within the body to provide skeletal mobility and have a characteristic structure adapted to provide a smooth almost frictionless surface for articulation. Pathologies of the synovial joint are an important cause of patient morbidity and can affect each of the constituent tissues. A common feature of these pathologies is degenerative changes in the structure of the tissue which is mediated, at least in part, by proteolytic activity. Most tissues of the synovial joint are composed primarily of extracellular matrix and key pathological roles in the degeneration of this matrix are performed by metalloproteinases such as matrix metallproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). However, other proteases such as cathepsin K are likely to play an important role, especially in bone turnover. In addition to the cleavage of structural proteins, proteolytic activities are employed to regulate the activity of other proteases, growth factors, cytokines and other inflammatory mediators. Proteases combine to form complex regulatory networks, the correct functioning of which is required for tissue homeostasis and the imbalance of which may be a feature of pathology. A precise understanding of the proteases involved in these networks is required for a true understanding of the associated pathology.

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“…In vivo, their activity and stability are influenced by environmental parameters, such as pH and ionic composition. Cathepsin S is known to be stable at neutral pH (60), whereas cathepsins K and L are relatively short lived (18,61). Macrophages circumvent this problem by utilizing a vacuolar-type H ϩ -ATPase to acidify the pericellular milieu where cathepsins are secreted (13).…”

Section: Discussionmentioning

confidence: 99%

Interaction between Human Cathepsins K, L, and S and Elastins

Novinec

Grass²,

Stark³

et al. 2007

Journal of Biological Chemistry

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Proteolytic degradation of elastic fibers is associated with a broad spectrum of pathological conditions such as atherosclerosis and pulmonary emphysema. We have studied the interaction between elastins and human cysteine cathepsins K, L, and S, which are known to participate in elastinolytic activity in vivo. The enzymes showed distinctive preferences in degrading elastins from bovine neck ligament, aorta, and lung. Different susceptibility of these elastins to proteolysis was attributed to morphological differences observed by scanning electron microscopy. Kinetics of cathepsin binding to the insoluble substrate showed that the process occurs in two steps. The enzyme is initially adsorbed on the elastin surface in a nonproductive manner and then rearranges to form a catalytically competent complex. In contrast, soluble elastin is bound directly in a catalytically productive manner. Studies of enzyme partitioning between the phases showed that cathepsin K favors adsorption on elastin; cathepsin L prefers the aqueous environment, and cathepsin S is equally distributed among both phases. Our results suggest that elastinolysis by cysteine cathepsins proceeds in cycles of enzyme adsorption, binding of a susceptible peptide moiety, hydrolysis, and desorption. Alternatively, the enzyme may also form a new catalytic complex without prior desorption and re-adsorption. In both cases the active center of the enzymes remains at least partly accessible to inhibitors. Elastinolytic activity was readily abolished by cystatins, indicating that, unlike enzymes such as leukocyte elastase, pathological elastinolytic cysteine cathepsins might represent less problematic drug targets. In contrast, thyropins were relatively inefficient in preventing elastinolysis by cysteine cathepsins.Elastic fibers are the key extracellular matrix component conferring elasticity to tissues such as blood vessels, lungs, and skin. The fibers are composed of a rubber-like network of highly stable and hydrophobic polymers of the protein elastin, associated with peripheral microfibrils (1, 2). Proteolytic degradation of elastic fibers leads to loss of tissue elasticity, which is associated with the development of different pathological conditions. A large repertoire of elastinolytic peptidases has been identified in human cells and tissues, including enzymes from four of the five catalytic classes of peptidases. The molecular mechanism underlying the process of elastinolysis has been thoroughly studied for human leukocyte elastase (HLE) 2 (3-9), a serine peptidase produced by neutrophils, whose activity has been associated with the development of atherosclerosis and pulmonary diseases (10, 11). In addition, two other elastinolytic serine peptidases are present in neutrophils, cathepsin G and myeloblastin (leukocyte proteinase 3) (12).Extracellular matrix degradation by monocyte-derived macrophages is because of the action of serine peptidases, matrix metalloproteases, and papain-like cysteine peptidases (cysteine cathepsins) (13-16). In inflammation, m...

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Mature Cathepsin L Is Substantially Active in the Ionic Milieu of the Extracellular Medium

Cited by 57 publications

References 0 publications

Diverse regulatory roles for lysosomal proteases in the immune response

Diverse regulatory roles for lysosomal proteases in the immune response

The role of proteases in pathologies of the synovial joint

Interaction between Human Cathepsins K, L, and S and Elastins

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