Serous Cavity Mast Cells Depend on the ROQUIN Paralogs

Mast cells are evolutionarily ancient immune cells located at strategic entry points for pathogens and allergens. Allergen exposure activates signal transduction pathways resembling those downstream of antigen receptors in T and B lymphocytes, leading to mast cell degranulation and cytokine secretion. The paralogous RNA-binding proteins ROQUIN-1 and ROQUIN-2 prevent aberrant T cell activation and differentiation and are cleaved upon antigen receptor engagement. Here, we investigated their roles in connective tissue mast cells using conditional gene knockout in mice. We show that ROQUIN-1 and ROQUIN-2 are dispensable for skin mast cell development and maintenance, while they are essential for serosal mast cells residing in the peritoneal and pleural cavities. Concurrent ablation of both paralogs did not affect mast cell degranulation in vitro and in vivo, nor did it alter activation-induced secretion of TNF and IL-6, cytokines that are regulated by ROQUIN proteins in other cell types. Furthermore, we globally define ROQUIN-regulated mRNAs in mast cells, and validate Runx1t1 and Ebi3 as indirect and Lfng as direct ROQUIN targets. Collectively, our results highlight the essential function of ROQUIN in connective tissue mast cells in serosal cavities.