Heterotrimeric G-protein Signaling Is Critical to Pathogenic Processes in Entamoeba histolytica

Dustin E. Bosch, Adam J. Kimple, Robin E. Muller, Patrick M. Giguère, Mischa Machius, Francis S. Willard, Brenda R. S. Temple, David P. Siderovski, William A. Petri
2012 PLoS Pathogens  
Heterotrimeric G-protein signaling pathways are vital components of physiology, and many are amenable to pharmacologic manipulation. Here, we identify functional heterotrimeric G-protein subunits in Entamoeba histolytica, the causative agent of amoebic colitis. The E. histolytica Ga subunit EhGa1 exhibits conventional nucleotide cycling properties and is seen to interact with EhGbc dimers and a candidate effector, EhRGS-RhoGEF, in typical, nucleotide-stateselective fashions. In contrast, a
more » ... al structure of EhGa1 highlights unique features and classification outside of conventional mammalian Ga subfamilies. E. histolytica trophozoites overexpressing wildtype EhGa1 in an inducible manner exhibit an enhanced ability to kill host cells that may be wholly or partially due to enhanced host cell attachment. EhGa1-overexpressing trophozoites also display enhanced transmigration across a Matrigel barrier, an effect that may result from altered baseline migration. Inducible expression of a dominant negative EhGa1 variant engenders the converse phenotypes. Transcriptomic studies reveal that modulation of pathogenesis-related trophozoite behaviors by perturbed heterotrimeric G-protein expression includes transcriptional regulation of virulence factors and altered trafficking of cysteine proteases. Collectively, our studies suggest that E. histolytica possesses a divergent heterotrimeric Gprotein signaling axis that modulates key aspects of cellular processes related to the pathogenesis of this infectious organism.
doi:10.1371/journal.ppat.1003040 pmid:23166501 pmcid:PMC3499586 fatcat:oxczrqtipvc43ch2sh6bj4ev2e