Natural killer (NK) cells are innate lymphocytes with cytolytic activity against target cells. NK cells produce specialized secretory lysosomes called lytic granules (LGs), which move along microtubules to the cytolytic synapse where they fuse with the plasma membrane to release cytotoxic proteins (a process called degranulation). The small GTPase Rab27a regulates the fusion of LGs at the synapse, and thus has a crucial role in degranulation. MADD is a Rab27a guanine nucleotide exchange factor (GEF) found in several cell types, but the GEF that regulates Rab27a activity in NK cells has not yet been described. In this study (Medlyn et al., 2024), Daniel Billadeau and colleagues investigate the role of MADD in degranulation via the activation of Rab27a in cytotoxic lymphocytes. The authors find that MADD associates with Rab27a on LGs, and they colocalize at the cytolytic synapse. Loss of either MADD or Rab27a expression in NK cells does not affect the processes upstream of LG fusion, but results in a similar significant reduction in degranulation and cytolytic activity. In addition, although loss of MADD does not affect the localization of Rab27a to LGs, it does impact the cellular levels of active Rab27a-GTP. Overall, this study demonstrates that MADD is required to activate Rab27a and induce the events involved in terminal fusion of LGs at the cytolytic synapse, identifying a key new regulatory element required for degranulation.
