The role of cathepsin X in the migration and invasiveness of T lymphocytes

Jevnikar, Zala; Obermajer, Nataša; Bogyo, Matthew; Kos, Janko

doi:10.1242/jcs.023721

Cited by 62 publications

(73 citation statements)

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“…As demonstrated in different types of immune cells, cathepsin X is translocated on the plasma membrane after activation stimuli such as PMA and LPS [27,32]. In the peri-membranous region of T cells it was found co-localized with LFA-1 and might therefore cleave the b 2 -cytoplasmic domain of LFA-1 in vivo [26]. Furthermore, a direct interaction between cathepsin X and b 2 integrin subunit has been confirmed by co-immunoprecipitation [32].…”

Section: Discussionmentioning

confidence: 82%

“…7D). Overexpression of cathepsin X in Jurkat T cells resulted in increased homotypic aggregation [26], but the presence of ICAM-1 reduced homotypic aggregation of these cells (our unpublished observation).To further investigate whether cathepsin X is involved in the conversion of high affinity LFA-1 (KIM127 ) LFA-1 conformation, the effect of cathepsin X neutralizing mAb 2F12 on the presence of different LFA-1 conformations was tested. The cells were left to migrate for 30 min on ICAM-1-coated slides in the absence or presence of mAb 2F12.…”

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confidence: 99%

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Cathepsin X cleaves the β2 cytoplasmic tail of LFA‐1 inducing the intermediate affinity form of LFA‐1 and α‐actinin‐1 binding

et al. 2009

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The motility of T cells depends on the dynamic spatial regulation of integrin-mediated adhesion and de-adhesion. Cathepsin X, a cysteine protease, has been shown to regulate T-cell migration by interaction with lymphocyte function associated antigen-1 (LFA-1). LFA-1 adhesion to the ICAM-1 is controlled by the association of actin-binding proteins with the cytoplasmic tail of the b 2 chain of LFA-1. Cleavage by cathepsin X of the amino acid residues S 769 , E 768 and A 767 from the C-terminal of the b 2 cytoplasmic tail of LFA-1 is shown to promote binding of the actin-binding protein a-actinin-1. Furthermore, cathepsin X overexpression reduced LFA-1 clustering and induced an intermediate affinity LFA-1 conformation that is known to associate with a-actinin-1. Increased levels of intermediate affinity LFA-1 resulted in augmented cell spreading due to reduced attachment of T cells to the ICAM-1-coated surface. Gradual cleavage of LFA-1 by cathepsin X enables the transition between intermediate and high affinity LFA-1, an event that is crucial for effective T-cell migration.Key words: a-Actinin-1 . b 2 Cytoplasmic tail . Cathepsin X . LFA-1 affinity . T-cell migration IntroductionIntegrins are a large family of a/b heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix adhesion and transduce signals bi-directionally across the plasma membrane. Lymphocyte function associated antigen-1 (LFA-1, a L b 2 , CD11a/CD18) belongs to the b 2 integrin subfamily and is constitutively expressed on all leukocytes. LFA-1 undergoes a dramatic conformational change that involves affinity regulation and cell surface clustering (valency regulation) during lymphocyte activation, which greatly increases the binding avidity (affinity1valency) for ligands such as ICAM-1, -2 and -3 [1, 2].LFA-1 can take up three conformations, a bent form and two extended forms. The bent form is inactive, whereas the extended forms, closed and open, exhibit intermediate and high affinities, respectively, for ICAM-1, depending on the angle between the hybrid and b-like I domains [3,4]. The extended conformations are recognized by mAb KIM 127 that binds to the epitope on the second EGF-like domain of the b 2 subunit, which is exposed when LFA-1 converts from the bent to the extended form [5,6]. Another antibody, mAb 24, recognizes solely the open, highaffinity conformation of LFA-1 [7].LFA-1 functions either by binding ligands through a process known as outside-in signaling or by binding cytoskeleton components for inside-out signaling. Although the a L and b 2 cytoplasmic tails of LFA-1 are relatively short, they play a pivotal role in these bi-directional signaling processes. For example, truncation of the b 2 cytoplasmic tail eliminates LFA-1 binding to 3 [15] that are the final effectors of inside-out signaling pathways. T-cell migration is a cyclic process that includes alternating integrin-mediated cell adhesion and de-adhesion, associated with regular activation and de-activation of integrins [16,17]. Accumulating...

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Section: Discussionmentioning

confidence: 82%

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confidence: 99%

Cathepsin X cleaves the β2 cytoplasmic tail of LFA‐1 inducing the intermediate affinity form of LFA‐1 and α‐actinin‐1 binding

et al. 2009

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“…Cysteine cathepsin protein levels were determined by ELISAs as reported previously [51]. Human recombinant CtsB [64], CtsS (donated by Dr. Boris Turk, Jožef Stefan Institute, SI), and CtsX [65] were used as standards.…”

Section: Determination Of Levels Of Cysteine Cathepsin Protein and Acmentioning

confidence: 99%

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

et al. 2012

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IntroductionThe ability of macrophages (Mfs) to progress to specific tissues, increase matrix remodeling, and induce angiogenesis is essential for their normal physiological function [1,2]. In addition, tissue infiltration of Mfs is also involved in pathological processes such as chronic inflammation, atherosclerosis, neurodegenerative disorders, and cancer progression [3]. The presence of Mfs Correspondence: Dr. Bojana Mirković e-mail: bojana.mirkovic@ffa.uni-lj.si within tumors is generally a marker of poor prognosis since they enhance angiogenesis and metastasis [4]. Furthermore, tumorassociated Mfs are emerging as essential matrix-remodeling cells during tumor-cell invasion. They have been reported to be present at high frequency at the invasive front of the tumor, where the breakdown of extracellular matrix (ECM) occurs [5]. Therefore, there is a great need to specifically control tissue infiltration of Mfs by targeting Mf migration-related molecules [6]. * These authors contributed equally to the present work. Eur. J. Immunol. 2012. 42: 3429-3441 Mf migration has been studied extensively in two dimensions (2D) on artificial substrates; however, in vivo Mfs migrate through physiological and pathological tissue and interact with the surrounding three-dimensional (3D) ECM, including basement membrane, collagen-rich interstitial matrices, and dense tissues such as tumors. Cells of different origins and/or at different differentiation stages use distinct mechanisms of cell motility in the 3D environment. In the mesenchymal mode, cells wider than the matrix pore size degrade the matrix via proteolytic and force-based matrix remodeling, thus migrating in a "path-generating" manner, while amoeboid cells squeeze through pre-existing pores in a proteaseindependent fashion in a "path-finding" mode [7,8]. The first 3D migration studies performed on cells of the immune system suggested that these cells migrate in a protease-independent fashion [7,9]. In contrast, a recent study demonstrated that Mfs adapt their migration strategy depending on the architecture of the 3D environment. In this study, Mfs were found to use the amoeboid migration mode in fibrillar collagen I and the mesenchymal migration mode in dense substrates, such as Matrigel and gelled collagen I [10].The invasion of cancer cells is facilitated by ECM-degrading invadopodia [11]. Podosomes are structures functionally similar to the invadopodia that are found in Mfs, osteoclasts, and DCs [12,13]. During migration on 2D surfaces [14], dot or ringlike podosomes form at the ventral surface of the migrating cells where they establish direct contact with the substratum and are also involved in matrix degradation [11]. Structurally, podosomes comprise a concentrated core of F-actin and actin-regulatory proteins [14]. Surrounding the core is a ring region that contains scaffolding-, signaling-, and integrin-binding proteins, including the typical focal adhesion proteins vinculin, talin, paxillin, and FAK [15]. When Mfs migrate in a 3D environment (i.e., migra...

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“…Several reports link cathepsin X with integrin-dependent cell adhesion, migration and events contingent on adhesion. For example, overexpression of the enzyme in Jurkat T cells enhanced cell polarisation and migration through 3-D matrices [73] (Fig. 1B).…”

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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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The role of cathepsin X in the migration and invasiveness of T lymphocytes

Cited by 62 publications

References 62 publications

Cathepsin X cleaves the β2 cytoplasmic tail of LFA‐1 inducing the intermediate affinity form of LFA‐1 and α‐actinin‐1 binding

Cathepsin X cleaves the β2 cytoplasmic tail of LFA‐1 inducing the intermediate affinity form of LFA‐1 and α‐actinin‐1 binding

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

Diverse regulatory roles for lysosomal proteases in the immune response

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