Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B<i>in vivo</i>

Pham, Christine; Ley, Timothy J.

doi:10.1073/pnas.96.15.8627

Cited by 368 publications

(314 citation statements)

References 48 publications

(46 reference statements)

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“…14 Also, genes known to be associated with the development of CMI were upregulated, including a range of chemoattractants (MIG, Crg-2, I-TAC, and RANTES) that attract activated and memory Th1 cells, 15,16 Cathepsin C that is required for activation of granzymes and plays a role in the expansion of CD8 T cell cytolytic activity, 17,18 and IFN-g inducible protein Mag-1 that accompanies Th1 cytokine expression in Toxoplasma gondi infected mice. 19 In addition, 13 types of GTP and 12 types of GBP-binding proteins were specifically induced in response to IFN-g.…”

Section: Resultsmentioning

confidence: 99%

Combinations of IFN-γand IL-4 induce distinct profiles of dendritic cell-associated immunoregulatory properties

et al. 2003

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Interferon gamma (IFN-g) and interleukin-4 (IL-4) are not only generated during cell-mediated immunity (CMI) and humoral immunity (HI), but are also generated by innate immune cells in response to pathogenic factors. How these cytokines differentially effect the development of dendritic cell (DC)-associated immunoregulatory properties from progenitor cells during innate immunity is unresolved. To address this we have utilized a homogeneous DC progenitor-like cell line, MTHC-D2, as a model to examine cytokine-induced maturation of DCs. By 6 h IFN-g induced genes that are important for antiviral activity and development of CMI, whereas IL-4 induced genes involved in cellular adhesion, uptake of extracellular antigen, suppression of cytotoxic T-cell responses, and that repair the extracellular matrix. By 48 h the cytokine stimulus had induced many properties characteristic of immature DCs; however, these were differentially effected by IFN-g and IL-4. IFN-g induced the greatest levels of costimulatory/ activation marker expression, and the highest levels of T-cell proliferation, whereas IL-4 induced the greatest levels of phagocytic activity. Stimulation of the cells with CD40 Ab enhanced the levels of costimulatory marker expression and T-cell stimulatory capacity of cells exposed to IFN-g, but had little effect on cells exposed to IL-4 in the absence of IFN-g.

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Section: Resultsmentioning

confidence: 99%

Combinations of IFN-γand IL-4 induce distinct profiles of dendritic cell-associated immunoregulatory properties

et al. 2003

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“…22,23 Paradoxically, the CLs could synthesize and store large amounts of PRF without any apparent detrimental consequence, even though the endoplasmic reticulum seems to provide Ca 2 þ concentrations suitable for membrane binding and pore formation. Granzymes and other toxic proteases are synthesized as zymogens and are typically activated only on reaching lysosome-like SGs; 24,25 in the cytosol of CLs, 'escaped' granzymes can be irreversibly inhibited by serpins (for example, human PI-9 or mouse SPI-6). [26][27][28][29] However, there does not seem to be any naturally occurring inhibitor for PRF.…”

Section: Perforin Biologymentioning

confidence: 99%

Perforin deficiency and susceptibility to cancer

et al. 2010

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Cytotoxic lymphocytes (CLs) are the killer cells that destroy intracellular pathogen-infected and transformed cells, predominantly through the cytotoxic granule-mediated death pathway. Soluble cytotoxic granule components, including pore-forming perforin and pro-apoptotic serine proteases, granzymes, synergize to induce unscheduled apoptosis of the target cell. A complete loss of CL function results in an aggressive immunoregulatory disorder, familial hemophagocytic lymphohistiocytosis, whereas a partial loss of function seems to be a factor strongly predisposing to hematological malignancies. This review discusses the pathological manifestations of CL deficiencies due to impaired perforin function and describes novel aspects of perforin biology. Cell Death and Differentiation (2010) 17, 607-615; doi:10.1038/cdd.2009; published online 15 January 2010Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, collectively called cytotoxic lymphocytes (CLs), kill virusinfected and transformed cells through a number of contactdependent mechanisms. 1,2 Engagement of death receptors by membrane-bound members of the TNF superfamily of death ligands is critical for maintaining lymphoid homeostasis in the host. By contrast, studies of gene deficiencies indicate that defects of the granule exocytosis pathway result in a failure to eliminate infected cells or those that pose a risk of subsequent malignancy. Although cytotoxic granules contain diverse toxins that together contribute to apoptosis induction, this review will deal exclusively with the critical role of the pore-forming protein perforin (PRF) as an essential enabler of target-cell apoptosis, and its more recently described role as a potential 'extrinsic' tumor suppressor.Perforin is a 67-kDa pore-forming protein that is stored and released from the secretory granules (SGs) of CLs along with a number of pro-apoptotic serine protease granzymes that display broad substrate specificities. 3 Following exocytic release, PRF and the granzymes are exposed to the neutral pH and calciumrich environment of the immune synapse. 4 After binding calcium through their C2 domains, PRF monomers acquire the ability to bind generic lipids in the target cell membrane, 5 and then coalesce into large transmembrane pores that permit the granzymes to access key death substrates in the cytosol. [6][7][8] Although the diverse apoptotic pathways triggered by granzymes have been extensively studied and are now understood in considerable detail, it is only of late that insights into the molecular and cellular functions of PRF have been even partly addressed.In this review, we will re-examine the pathological consequences of PRF deficiency, both in mice and humans. In doing so, important differences in PRF biology between these species will be described. We will discuss the pathogenic effect of a number of recently described missense mutations of human PRF. In particular, although the complete absence of PRF function typically results in an aggressive, fatal immunoregulatory disorder of ea...

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“…Mice lacking cathepsin C fail to activate neutrophil and mast cell granule proteases [57,58]. Defects in cytotoxic T-cell function have also been reported in these mice [59]. However, recent studies indicate that residual granzyme B (but not granzyme A) activity in cytotoxic T cells was observed in the absence of cathepsin C and that this was sufficient to control some viral infections [60].…”

Section: Activation Of Granule Serine Proteasesmentioning

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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Dipeptidyl peptidase I is required for the processing and activation of granzymes A and Bin vivo

Cited by 368 publications

References 48 publications

Combinations of IFN-γand IL-4 induce distinct profiles of dendritic cell-associated immunoregulatory properties

Combinations of IFN-γand IL-4 induce distinct profiles of dendritic cell-associated immunoregulatory properties

Perforin deficiency and susceptibility to cancer

Diverse regulatory roles for lysosomal proteases in the immune response

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