PUBLISHED PMID: 19833722 IL-1? is an important pro-inflammatory cytokine that is secreted by unconventional means in a caspase-1-dependent manner. Using a one-step immunoprecipitation approach to isolate endogenous caspase-1 from the monocytic THP1 cell line, we identified previously undescribed binding partners using mass spectrometry. One of the proteins identified was Rab39a, a member of the Rab GTPase family, a group of proteins which have important roles in protein trafficking and secretion. We confirmed by co-immunoprecipitation that Rab39a binds caspase-1. Knock-down of Rab39a with siRNA resulted in diminished levels of secreted IL-1? but had no effect on induction of pro-IL-1? mRNA by LPS. Rab39a contains a highly conserved caspase-1 cleavage site and was cleaved in the presence of recombinant caspase-1 or LPS. Finally, over-expression of Rab39a results in an increase in IL-1? secretion and furthermore, over-expression of a Rab39a construct lacking the caspase-1 cleavage site, leads to an additional increase in IL-1? secretion. Altogether, our findings show that Rab39a interacts with caspase-1 and suggests that Rab39a functions as a trafficking adaptor linking caspase-1 to IL-1? secretion. This work was supported by a grant from the Health Research Board and Science Foundation Ireland