Cysteine protease cathepsin X modulates immune response via activation of β<sub>2</sub> integrins

Obermajer, Nataša; Repnik, Urška; Jevnikar, Zala; Turk, Boris; Kreft, Marko; Kos, Janko

doi:10.1111/j.1365-2567.2007.02740.x

Cited by 52 publications

(40 citation statements)

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“…These motility-associated morphological changes also depend on the LFA-1 affinity and the LFA-1-cytoskeleton association [37]. Additionally, we showed that cathepsin X promotes proliferation of T cells [38]. This is consistent with the study of Wang et al demonstrating that LFA-1 affinity regulation is crucial for the activation and proliferation of naïve T cells [39].…”

Section: Discussionsupporting

confidence: 81%

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: Discussionsupporting

confidence: 81%

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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“…8,44 The role of CPs in AAA pathophysiology extends beyond degradation of structural extracellular matrix; these enzymes also contribute to a number of processes through other substrates such as cytokines, integrins, and other proteases. [45][46][47] We recently suggested a mechanism of microvessel growth stimulation by CatS by generating highly proangiogenic laminin-5 ␥2 fragments. 29 Consistent with this finding, we detected increased levels of such laminin-5 ␥2 fragments, colocalization of these proteins with extensive microvascularization, and strong correlation between these two variables (r 2 ϭ 0.8653, P Ͻ 0.001) in AAA lesions of CystC Ϫ/Ϫ ApoE Ϫ/Ϫ mice ( Figure 5, A-D), supporting a role for CPs in angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Cystatin C Deficiency Promotes Inflammation in Angiotensin II–Induced Abdominal Aortic Aneurisms in Atherosclerotic Mice

Schulte

Sun

Libby

et al. 2010

The American Journal of Pathology

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“…Initial reports have indicated that it can also act as a peptidyl-dipeptidase (9, 58) ; these indications were, however, not confirmed in later studies (59,60) . It is highly expressed in the immune system where it has been shown to regulate cell behavior and differentiation (61,62) . The cathepsin X propeptide contains an integrin-binding RGD sequence and its association with cell surface integrins has been shown to regulate cell adhesion (63) .…”

Section: Cathepsin Xmentioning

confidence: 99%

Papain-like peptidases: structure, function, and evolution

Novinec

Lenarčič²

2013

BioMolecular Concepts

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Papain-like cysteine peptidases are a diverse family of peptidases found in most known organisms. In eukaryotes, they are divided into multiple evolutionary groups, which can be clearly distinguished on the basis of the structural characteristics of the proenzymes. Most of them are endopeptidases; some, however, evolved into exopeptidases by obtaining additional structural elements that restrict the binding of substrate into the active site. In humans, papain-like peptidases, also called cysteine cathepsins, act both as non-specific hydrolases and as specific processing enzymes. They are involved in numerous physiological processes, such as antigen presentation, extracellular matrix remodeling, and hormone processing. Their activity is tightly regulated and dysregulation of one or more cysteine cathepsins can result in severe pathological conditions, such as cardiovascular diseases and cancer. Other organisms can utilize papainlike peptidases for different purposes and they are often part of host-pathogen interactions. Numerous parasites, such as Plasmodium and flukes, utilize papain-like peptidases for host invasion, whereas plants, in contrast, use these enzymes for host defense. This review presents a state-of-the-art description of the structure and phylogeny of papain-like peptidases as well as an overview of their physiological and pathological functions in humans and in other organisms.

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Cysteine protease cathepsin X modulates immune response via activation of β₂ integrins

Cited by 52 publications

References 35 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

Cystatin C Deficiency Promotes Inflammation in Angiotensin II–Induced Abdominal Aortic Aneurisms in Atherosclerotic Mice

Papain-like peptidases: structure, function, and evolution

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Cysteine protease cathepsin X modulates immune response via activation of β2 integrins

Cited by 52 publications

References 35 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

Cystatin C Deficiency Promotes Inflammation in Angiotensin II–Induced Abdominal Aortic Aneurisms in Atherosclerotic Mice

Papain-like peptidases: structure, function, and evolution

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Cysteine protease cathepsin X modulates immune response via activation of β₂ integrins