Cathepsin B Is Involved in the Trafficking of TNF-α-Containing Vesicles to the Plasma Membrane in Macrophages

Ha, Soon Duck; Martins, Andrew J.; Khazaie, Khashayarsha; Han, Jiahuai; Chan, Bosco M.C.; Kim, Sung Ouk

doi:10.4049/jimmunol.181.1.690

Cited by 112 publications

(90 citation statements)

References 45 publications

(44 reference statements)

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“…Nonlysosomal cathepsin B has been implicated in both pathological and physiological processes. In cells of the monocyte/macrophage lineage, cytosolic cathepsin B was suggested to regulate secretion of tumor necrosis factor-␣ induced by inflammatory stimuli (55). Further, multiple reports have implicated nonlysosomal cathepsin B in promoting myoblast fusion.…”

Section: Discussionmentioning

confidence: 99%

Regulated Proteolysis of Nonmuscle Myosin IIA Stimulates Osteoclast Fusion

McMichael

Wysolmerski

Lee

2009

Journal of Biological Chemistry

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The nonmuscle myosin IIA heavy chain (Myh9) is strongly associated with adhesion structures of osteoclasts. In this study, we demonstrate that during osteoclastogenesis, myosin IIA heavy chain levels are temporarily suppressed, an event that stimulates the onset of cell fusion. This suppression is not mediated by changes in mRNA or translational levels but instead is due to a temporary increase in the rate of myosin IIA degradation. Intracellular activity of cathepsin B is significantly enhanced at the onset of osteoclast precursor fusion, and specific inhibition of its activity prevents myosin IIA degradation. Further, treatment of normal cells with cathepsin B inhibitors during the differentiation process reduces cell fusion and bone resorption capacity, whereas overexpression of cathepsin B enhances fusion. Ongoing suppression of the myosin IIA heavy chain via RNA interference results in formation of large osteoclasts with significantly increased numbers of nuclei, whereas overexpression of myosin IIA results in less osteoclast fusion. Increased multinucleation caused by myosin IIA suppression does not require RANKL. Further, knockdown of myosin IIA enhances cell spreading and lessens motility. These data taken together strongly suggest that base-line expression of nonmuscle myosin IIA inhibits osteoclast precursor fusion and that a temporary, cathepsin B-mediated decrease in myosin IIA levels triggers precursor fusion during osteoclastogenesis.The final stages of osteoclastogenesis involve fusion of differentiated precursors from the monocyte/macrophage lineage (1). Although the membrane structural components regulating preosteoclast fusion are not well understood, in recent years a number of candidate cell surface molecules have been implicated, including receptors CD44 (2, 3), CD47 and its ligand macrophage fusion receptor (also known as signal regulatory protein ␣) (4 -6), the purinergic receptor P2X 7 (7), and the disintegrin and metalloproteinase ADAM8 (8). A recently identified receptor, the dendritic cell-specific transmembrane protein, is essential for osteoclast fusion both in vitro and in vivo (9, 10). More recently, the d2 subunit of proton-translocating vacuolar proton-translocating ATPases, a membrane subunit isoform expressed predominantly in osteoclasts, similarly was demonstrated to be required for fusion in vitro and in vivo (11). However, elucidation of the mechanisms by which these molecules may mediate cell fusion has proved to be difficult.The mammalian class II myosin family consists of distinct isoforms expressed in skeletal, smooth, and cardiac muscle, as well as three nonmuscle forms designated IIA, IIB,. Although all class II molecules are composed of two heavy chains, two essential light chains, and two regulatory chains, their unique activities are a function of their particular heavy chain isoforms. Although the nonmuscle heavy chain isoforms share extensive structural homology, they have been shown to demonstrate distinct patterns of expression (15-18), enzyme kinetics and activ...

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Section: Discussionmentioning

confidence: 99%

Regulated Proteolysis of Nonmuscle Myosin IIA Stimulates Osteoclast Fusion

McMichael

Wysolmerski

Lee

2009

Journal of Biological Chemistry

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“…It's known that the activation of NLRP3 infl ammasome by a variety of stimuli depends on lysosomal rupture, K + effl ux and/ or production of reactive oxygen species (ROS) (Ha et al, 2008;Tschopp and Schroder, 2010). To further explore the mechanism underlying IL-1β induction by T. schoenleinii, we fi rst utilized CA-074 Me to inhibit activity of Cathepsin B, which is usually produced due to lysosomal rupture.…”

Section: T Schoenleinii Triggers Il-1β Production From Human Monocytesmentioning

confidence: 99%

Human pathogenic fungus Trichophyton schoenleinii activates the NLRP3 inflammasome

Mao

et al. 2013

Protein Cell

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The fungus Trichophyton schoenleinii (T. schoenleinii) is the causative agent of Trichophytosis and Tinea favosa of the scalp in certain regions of Eurasia and Africa. Human innate immune system plays an important role in combating with various pathogens including fungi. The inflammasome is one of the most critical arms of host innate immunity, which is a protein complex controlling maturation of IL-1β. To clarify whether T. schoenleinii is able to activate the infl ammasome, we analyzed human monocytic cell line THP-1 for IL-1β production upon infection with T. schoenleinii strain isolated from Tinea favosa patients, and rapid IL-1β secretion from THP-1 cells was observed. Moreover, applying competitive inhibitors and gene specifi c silencing with shRNA, we found that T. schoenleinii induced IL-1β secretion, ASC pyroptosome formation as well as caspase-1 activation were all dependent on NLRP3. Cathepsin B activity, ROS production and K + effl ux were required for the infl ammasome activation by T. schoenleinii. Our data thus reveal that the NLRP3 infl ammasome plays an important role in host defense against T. schoenleinii, and suggest that manipulating NLRP3 signaling can be a novel approach for control of diseases caused by T. schoenleinii infection.

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“…A recent study identified an additional requirement for cathepsin B, at least for a proportion of TNF-a release in some macrophages. Ablation of cathepsin B led to accumulation of the membrane bound TNF-a pro-form in intracellular vesicles implying a possible role for cathepsin B in fusion of these vesicles with the plasma membrane [50]. The relevant substrates for cathepsin B were not identified; therefore, it remains to be established whether cathepsin B is acting within the endosome/lysosome compartment or within the cytosol.…”

Section: Reciprocal Relationships Between Cytokines and Lysosomal Catmentioning

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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Cathepsin B Is Involved in the Trafficking of TNF-α-Containing Vesicles to the Plasma Membrane in Macrophages

Cited by 112 publications

References 45 publications

Regulated Proteolysis of Nonmuscle Myosin IIA Stimulates Osteoclast Fusion

Regulated Proteolysis of Nonmuscle Myosin IIA Stimulates Osteoclast Fusion

Human pathogenic fungus Trichophyton schoenleinii activates the NLRP3 inflammasome

Diverse regulatory roles for lysosomal proteases in the immune response

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