title: Secretory lysosomes of mouse mast cells store and exocytose active caspase-3 in a strictly granzyme B dependent manner.
abstract: In this study, we report that cytoplasmic granules from in vivo and in vitro derived mouse mast cells (MCs) contain active granzyme B (gzmB) and caspase-3, which is consistent with recent findings. Studying WT and gzmB-deficient mice, we observed that BM-derived MCs (BMMCs) from both strains contain cytosolic pro-caspase-3, but only WT BMMCs expressed active caspase-3 limited to their secretory lysosomes. Confocal microscopy revealed colocalization of active caspase-3 and gzmB in these cytoplasmic granules. The combined data demonstrate that the generation and storage of active caspase-3 is gzmB-dependent. The finding that BMMCs secrete caspase-3 and gzmB after Ag stimulation suggests that both proteases contribute to extracellular MC-mediated proteolytic events. Although the extracellular function of MC-derived caspase-3 remains unclear, we show that BMMC-secreted caspase-3 cleaves IL-33, a cytokine that contributes to the development of asthma and arthritis. We also show that an in vitro propagated cytolytic T-lymphocyte line constitutively expresses gzmB together with active caspase-3, suggesting a novel interaction of these proteases in the execution of multiple innate and adaptive immune responses.
authors.affiliation: Institute of Biochemistry and Molecular Immunology, University Clinic, RWTH Aachen University, Aachen, Germany.
authors.forename: Carolin N
authors.initials: CN
authors.lastname: Zorn
authors.forename: Julian
authors.initials: J
authors.lastname: Pardo
authors.forename: Praxedis
authors.initials: P
authors.lastname: Martin
authors.forename: Marcel
authors.initials: M
authors.lastname: Kuhny
authors.forename: Markus M
authors.initials: MM
authors.lastname: Simon
authors.forename: Michael
authors.initials: M
authors.lastname: Huber
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology; D000818:Animals; D000941:Antigens / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D005089:Exocytosis / Q000235:genetics / Q000276:immunology*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology; D053804:Granzymes / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000502:physiology; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis
chemical_list: D000941:Antigens; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D053804:Granzymes; C509214:Gzmb protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Caspase‐3; Cytotoxic T lymphocytes; Effector function; Granzyme B; Inflammation