Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most abundant autoreactive T cells in patients with Goodpasture's disease are specific for peptides in the autoantigen that have high affinity for the disease-associated HLA class II molecule, DR15. How can such T cells escape self-tolerance mechanisms? This study showed that these peptides are highly susceptible to destruction in the earliest stages of antigen processing, and some must be cleaved for antigen digestion to be possible ("unlocking"). Goodpasture autoantigen [collagen alpha3(IV)NC1; approximately 31 kD] that was incubated with B cell lysosomes was cleaved within a few minutes to form approximately 9- and approximately 22-kD fragments, then increasing quantities of smaller peptides. The processing was completely abrogated by pepstatin A, a specific inhibitor of cathepsin D/E, even though lysosomal extracts contain a rich array of proteases. Purified cathepsin D generated the same major alpha3(IV)NC1 fragments as entire lysosomes, suggesting that cathepsin D cleavages are required to initiate alpha3(IV)NC1 processing. The initial unlocking cleavages destroyed two major self-epitopes, and subsequent preferred cleavages destroyed all of the other T cell epitopes that are recognized by most patients' autoreactive T cells. The responses of T cell clones that are specific for a major disease-associated peptide to antigen-pulsed intact antigen-presenting cells were substantially enhanced by pepstatin A treatment. Therefore, cathepsin D activity significantly diminishes presentation of alpha3(IV)NC1 peptides that are recognized by patients' T cells by destroying the peptides in early processing. These observations can explain why the mature T cell repertoire includes reactivity toward these self-peptides and suggests that a key factor in disease initiation is likely to be a shift in antigen processing.
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PMID:Presentation of the Goodpasture autoantigen requires proteolytic unlocking steps that destroy prominent T cell epitopes. 1728 25

HLA class II-restricted antigen (Ag) processing and presentation are important for the activation of CD4+ T cells, which are the central orchestrating cells of immune responses. The majority of melanoma cells either expresses, or can be induced to express, HLA class II proteins. Thus, they are prime targets for immune mediated elimination by class II-restricted CD4+ T cells. We have previously shown that human melanoma cells lack an important enzyme, gamma interferon-inducible lysosomal thiol-reductase (GILT), capable of perturbing immune recognition of these tumors. Here, we show that GILT expression in human melanoma cells enhances Ag processing and presentation via HLA class II molecules. We also show that GILT expression influences the generation of active forms of cysteinyl proteases, cathepsins B, L and S, as well as an aspartyl protease cathepsin D in melanoma cells. Mechanistic studies revealed that GILT does not regulate acidic cathepsins at the transcriptional level; rather it colocalizes with the cathepsins and influences HLA class II Ag processing. GILT expression in melanoma cells also elevated HLA-DM molecules, which favor epitope loading onto class II in the endolysosomal compartments, enhancing CD4+ T cell recognition. These data suggest that GILT-expressing melanoma cells could prove to be very promising for direct antigen presentation and CD4+ T cell recognition, and may have direct implications for the design of cancer vaccines.
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PMID:Gamma-IFN-inducible-lysosomal thiol reductase modulates acidic proteases and HLA class II antigen processing in melanoma. 1834 23