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, for the first time, if Rab46 plays a role in mast cell function. We demonstrate, 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 subtype. This initial insight into the contribution of Rab46 to mast cell function, and the understanding of the role of Rab46 in stimuli-dependent trafficking in other cell types, necessitates further investigations of Rab46 in mast cell granular trafficking so that novel and specific therapeutic targets for treatment of the diverse pathologies mediated by mast cells can be developed.

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“…rs887304 is located at the 3' UTR of CRACR2A but is intronic in the Rab46 coding region and could potentially regulate isoform expression (https://www.ensembl.org/Homo_sapiens/Gene/Variation_Gene/Table?db=core;g=ENSG00 000130038;r=12:3606633-3764819). CRACR2A has been shown to be a regulator of storeoperated calcium in T-cells 22 whilst Rab46 regulates the trafficking of unique granules in endothelial cells 23 and differential secretion in mast cells 24 . In endothelial cells, Rab46 acts as a brake to prevent the secretion of pre-stored pro-inflammatory components in response to non-thrombotic stimuli.…”