The Expression and Function of Cathepsin E in Dendritic Cells

Abstract

Cathepsin E is an aspartic proteinase that has been implicated in Ag processing within the class II MHC pathway. In this study, we document the presence of cathepsin E message and protein in human myeloid dendritic cells, the preeminent APCs of the immune system. Cathepsin E is found in a perinuclear compartment, which is likely to form part of the endoplasmic reticulum, and also a peripheral compartment just beneath the cell membrane, with a similar distribution to that of Texas Red-dextran within 2 min of endocytosis. To investigate the function of cathepsin E in processing, a new soluble targeted inhibitor was synthesized by linking the microbial aspartic proteinase inhibitor pepstatin to mannosylated BSA via a cleavable disulfide linker. This inhibitor was shown to block cathepsin D/E activity in cell-free assays and within dendritic cells. The inhibitor blocked the ability of dendritic cells from wild-type as well as cathepsin D-deficient mice to present intact OVA, but not an OVA-derived peptide, to cognate T cells. The data therefore support the hypothesis that cathepsin E has an important nonredundant role in the class II MHC Ag processing pathway within dendritic cells.

Differential Regulation of the Nature and Functions of Dendritic Cells and Macrophages by Cathepsin E

“…Surprisingly, however, while the ability of macrophages to present OVA and its peptide to T cells was markedly decreased by cathepsin E deficiency, that of DCs was inversely enhanced by the absence of cathepsin E. Recently, Moss et al (10) reported that the presentation of two different myoglobin T cell epitopes in DCs was enhanced rather than hindered by the lack of cathepsin D. They also demonstrated that the residual processing activity found in the subcellular fraction of DCs deficient in cathepsin D was completely inhibited by pepstatin, thus suggesting that aspartic proteases besides cathepsin D expressed in DCs could be involved in myoglobin Ag presentation and that the reduced activity by cathepsin D deficiency would produce optimal conditions for its processing and presentation. Chain et al (24) also reported that the ability of DCs from wild-type and cathepsin D-deficient mice to present intact OVA, but not an OVA-derived peptide, to cognate T cells was completely blocked by the microbial aspartic proteinase inhibitor pepstatin-conjugated to mannosylated BSA, which could inhibit cathepsin D/E activity within the cells. Taken together, our data strongly suggest that reduced aspartic proteinase activities resulting from the absence of cathepsin E in DCs are closer to the optimum level required for OVA Ag presentation.…”

Hypochlorous Acid: A Natural Adjuvant That Facilitates Antigen Processing, Cross-Priming, and the Induction of Adaptive Immunity

“…Native OVA itself is highly resistant to proteolytic degradation by either trypsin or cathepsin E, an aspartic proteinase required for OVA processing by DCs (18). In contrast, OVA Cl I is digested by both cathepsin E (Fig.…”

Cathepsin E (EC 3.4.23.34) — a review

“…In a human organism, cathepsin E occurs in: erythrocytes, thymus, dendritic cells, epithelial M cells, microglia cells, Langerhans cells, lymphocytes, epithelium of gastrointestinal tract, urinary bladder, lungs, osteoclasts, spleen and lymphatic nodes [9][10][11][12][13][14]. However, it does not occur in human neutrophiles or bovine erythrocytes [15] (Table 2).…”