Rab27 is a member of the Rab family of Ras-like GTPases and is expressed in two isoforms,
Rab27a and Rab27b that share 72% amino acid identity. Previous studies have suggested
Rab27a and Rab27b to regulate inflammation through exocytosis in a variety of leukocytes
including T lymphocytes, NK cells, mast cells and neutrophils. A key process in inflammation
is mast cell secretion, a process in which Rab27b has been established as a positive
regulator but the role of Rab27a remains unclear. In this study we confirm that in response
to IgE crosslinking, Rab27a appears to play a negative role in secretion, however Rab27a was
observed to promote secretion in absence of Rab27b, so this effect is likely due to
abnormally distributed cortical F-actin and enhanced granule docking in absence of Rab27a.
Furthermore Rab27a may exert this regulation through effector Melanophilin. We also
confirm that the effector Munc13-4 is important for promoting mast cell secretion, likely
through interaction with both Rab27a and Rab27b.
Rab27 has also been suggested to regulate inflammation by promoting granule secretion in
neutrophils. Here we find that Rab27a was localised to structures at the uropod and that
Rab27a deficient neutrophils display defective chemotaxis due to impaired uropod release.
Inhibition of extracellular serine proteases inhibited wild-type but not Rab27a deficient
neutrophil chemotaxis suggesting that defective protease secretion may underlie Rab27a
deficient neutrophil chemotaxis defect. Analysis of αMβ2 integrin subunit CD11b after
chemokine stimulation revealed that CD11b surface expression was sustained on Rab27a
deficient neutrophils compared to wild-type, suggesting that cleavage of CD11b may be
impaired. Inhibition of other proteins known to promote primary granule secretion, Rab27b
and Rab27 effectors Slp1 and Munc13-4 also impaired neutrophil chemotaxis. Together
these data suggest that Rab27a promotes uropod detachment through release of proteases
contained in primary granules to promote neutrophil chemotaxis.