Diverse regulatory roles for lysosomal proteases in the immune response

Abstract

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...

Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

“…5, Supplementary Data 6). This is noteworthy, as lysosomes have been shown to play pivotal roles in both sensing and effector function of innate immune cells, our results suggest that there is a genetic contribution to these pathways 8,9 . In the following we focused on eQTLs unique to TLR4 signalling, both under absolute and differential expression, and refer to them as immune response eQTLs or iQTLs.…”

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

“…Nef is associated with lysosomes in macrophages where it colocalizes with cathepsin D. Because p61Hck activation has been associated with mobilization and exocytosis of lysosomes (29,30,47,(79)(80)(81)(82), it is conceivable that lysosomes, which contain several enzyme subsets, including proteases, hydrolases, and v-ATPase, could facilitate the cleavage of surface proteins and glycocalyx from opposite cells to interact more closely and hence facilitate cell fusion. Additionally, lysosomal proteases could modulate surface receptor activity and signaling involved in cell-cell fusion (53,68,69,(83)(84)(85). Lysosomal proteases have been implicated in the formation of myotubes (60,61) and found in the secretome of HIV-1-infected giant human macrophages (86).…”

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