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

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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 Gα subunit EhGα1 exhibits conventional nucleotide cycling properties and is seen to interact with EhGβγ dimers and a candidate effector, EhRGS-RhoGEF, in typical, nucleotide-state-selective fashions. In contrast, a crystal structure of EhGα1 highlights unique features and classification outside of conventional mammalian Gα subfamilies. E. histolytica trophozoites overexpressing wildtype EhGα1 in an inducible manner exhibit an enhanced ability to kill host cells that may be wholly or partially due to enhanced host cell attachment. EhGα1-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 EhGα1 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 G-protein signaling axis that modulates key aspects of cellular processes related to the pathogenesis of this infectious organism.

Original languageEnglish
Article numbere1003040
JournalPLoS Pathogens
Volume8
Issue number11
DOIs
StatePublished - Nov 2012

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    Bosch, D. E., Kimple, A. J., Muller, R. E., Giguère, P. M., Machius, M., Willard, F. S., Temple, B. R. S., & Siderovski, D. P. (2012). Heterotrimeric G-protein Signaling Is Critical to Pathogenic Processes in Entamoeba histolytica. PLoS Pathogens, 8(11), [e1003040]. https://doi.org/10.1371/journal.ppat.1003040