Rab46: a novel player in mast cell function

Abstract

Mast cells are infamous for mediating allergic and inflammatory diseases due to their capacity of rapidly releasing a wide range of inflammatory mediators stored in cytoplasmic granules. However, mast cells also have several important physiological roles that involves selective and agonist-specific release of these active mediators. Whilst a filtering mechanism at the plasma membrane could regulate selective release of some cargo, the plethora of stored cargo and the diversity of mast cell functions suggests the existence of granule subtypes with distinct trafficking pathways. The molecular mechanisms underlying differential trafficking and exocytosis of these granules are not known, neither is it clear how granule trafficking is coupled to the stimulus. In endothelial cells, a Rab GTPase, Rab46, responds to histamine but not thrombin signals, and this regulates the trafficking of a subpopulation of endothelial-specific granules. Here, we sought to explore if Rab46 has a similar function in mast cells. We demonstrate, for the first time, that Rab46 is highly expressed in human and murine mast cells and Rab46 genetic deletion has an effect on mast cell degranulation that depends on both stimuli and mast cell developmental stage. Rab46 could therefore be an important regulator of stimuli-coupled responses in mast cells and future studies will seek to understand these mechanisms in order to develop novel and specific therapeutic targets for treatment of the diverse pathologies mediated by mast cells.