Transgenic mice that possess a disrupted mast cell protease 5 (MMCP-5) gene can not store carboxypeptidase a (MMC-CPA) protein in their granules

Mouse MC express varied combinations of mMC-CPA and at least four lineage-specific chymases. Using a homologous recombination approach, transgenic mice were derived that possess a disrupted mMCP-5 gene. The disruption of the mMCP-5 gene did not alter the granulation of the mMCP-r/mMCP-2population of MC that increase in number in the intestinal mucosa of helminth-infected mice. However, the populations of MC found in the skin, ear, muscle, and peritoneal cavity of these mice were poorly granulated and lacked mMC-CPA protein. Bone marrow-derived MC were readily developed in vitro from the transgenic mice using IL-3. These MC contained high steady-state levels of mMC-CPA mRNA but no mMC-CPA protein, indicating that mMCP-5 protein itself is needed to target translated mMC-CPA to the secretory granule or to protect the latter neutral protease from autolysis. The expression of granule proteases in MC is regulated at the transcriptional level and at the post-transcriptional level via differential stabilization of the individual protease mRNAs. This is the first example where the expression of one granule protease dramatically effects another at the post-translational level. The MC is therefore the first hematopoietic cell found to use three different control mechanisms to ensure specific ratios of proteases in its granules. (Funded by HL-36I10.).