Vesicular trafficking mechanisms of immune cells.

The importance of Rab GTPases

The small GTPase Rab27a plays a central role in the regulation of exocytosis. Rab27a is the only Rab directly associated with a human genetic disease, the immunodeficiency Griscelli syndrome (GS). Deficiency of the Rab27a effector Munc13-4 is also associated with the human disease Familial Hemophagocytic Lymphohisticytosis type 3 (FHL-3). Patients with GS and FHL-3 develop an immunodeficiency disorder characterized by malfunction of cytotoxic T-lymphocytes and impaired natural killer cell function. We have recently shown that Rab27a and its counterpart effectors ­­coordinate the exocytic dynamics of neutrophil granules. Our studies aim to elucidate the differential mechanisms underlying the regulation of granule mobilization to the plasma membrane and to the phagosome in neutrophils using genetic and cellular biology approaches. One of our long-term goals is to develop molecular therapeutic strategies to prevent uncontrolled release of neutrophil granule cargo proteins to prevent inflammation without affecting the innate and adaptive immune responses.