MADD regulates natural killer cell degranulation through Rab27a activation.

Natural killer (NK) cells have the ability to lyse other cells through the release of lytic granules (LG). This is in part mediated by the small GTPase Rab27a, which was first identified to play a critical role in degranulation through the study of patients harboring mutations in the gene encoding Rab27a. However, the guanine nucleotide exchange factor (GEF) regulating the activation of Rab27a in cytotoxic lymphocytes was unknown. Here we show that knockout of MADD significantly decreased GTP-bound Rab27a in both resting and stimulated NK cells, and MADD-deficient NK cells and CD8+ T cells displayed severely reduced degranulation and cytolytic ability, similar to that seen with Rab27a deficiency. Consistent with this, MADD KO T NK cells have a substantial reduction in active Rab27a, which was also suppressed following activating receptor signaling. While MADD colocalizes with Rab27a on lytic granules and is enriched at the cytolytic synapse, the loss of MADD does not impact Rab27a association with lytic granules or their recruitment to the cytolytic synapse. Together our results demonstrate an important role for MADD in cytotoxic lymphocyte killing.