Rab39a binds caspase-1 and is required for caspase-1-dependent interleukin-1β secretion

Abstract

Interleukin-1β (IL-1β) 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 that have important roles in protein trafficking and secretion. We confirmed by co-immunoprecipitation that Rab39a binds caspase-1. Knock down of Rab39a with small interfering RNA resulted in diminished levels of secreted IL-1β but had no effect on induction of pro-IL-1β mRNA by lipopolysaccharide. Rab39a contains a highly conserved caspase-1 cleavage site and was cleaved in the presence of recombinant caspase-1 or lipopolysaccharide. Finally, overexpression of Rab39a results in an increase in IL-1β secretion, and furthermore, overexpression of a Rab39a construct lacking the caspase-1 cleavage site leads to an additional increase in IL-1β secretion. Altogether, our findings show that Rab39a interacts with caspase-1 and suggest that Rab39a functions as a trafficking adaptor linking caspase-1 to IL-1β secretion. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.