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

doi:10.1371/journal.ppat.1003040

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Heterotrimeric G-protein signaling is critical to pathogenic processes in Entamoeba histolytica

Journal article

Open access

Peer reviewed

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 and David P Siderovski

PLoS pathogens, Vol.8(11), pp.e1003040-e1003040

2012

DOI: 10.1371/journal.ppat.1003040

PMCID: PMC3499586

PMID: 23166501

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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.

Animals

CHO Cells

Cricetinae

Cricetulus

Crystallography, X-Ray

Entamoeba histolytica - enzymology

Entamoeba histolytica - genetics

Entamoeba histolytica - immunology

Entamoebiasis - enzymology

Entamoebiasis - genetics

Entamoebiasis - immunology

Gene Expression Regulation - immunology

GTP-Binding Protein alpha Subunits - chemistry

GTP-Binding Protein alpha Subunits - genetics

GTP-Binding Protein alpha Subunits - immunology

Guanine Nucleotide Exchange Factors - chemistry

Guanine Nucleotide Exchange Factors - genetics

Guanine Nucleotide Exchange Factors - immunology

Humans

Jurkat Cells

Protein Structure, Tertiary

Protozoan Proteins - chemistry

Protozoan Proteins - genetics

Protozoan Proteins - immunology

Rho Guanine Nucleotide Exchange Factors

Transcription, Genetic - immunology

Virulence Factors - biosynthesis

Virulence Factors - chemistry

Virulence Factors - immunology

Details

Title: Subtitle: Heterotrimeric G-protein signaling is critical to pathogenic processes in Entamoeba histolytica
Creators: Dustin E Bosch - University of North Carolina at Chapel Hill
Adam J Kimple - University of North Carolina at Chapel Hill
Robin E Muller - University of North Carolina at Chapel Hill
Patrick M Giguère - University of North Carolina at Chapel Hill
Mischa Machius - University of North Carolina at Chapel Hill
Francis S Willard - University of North Carolina at Chapel Hill
Brenda R S Temple
David P Siderovski - West Virginia University
Resource Type: Journal article
Publication Details: PLoS pathogens, Vol.8(11), pp.e1003040-e1003040
DOI: 10.1371/journal.ppat.1003040
PMID: 23166501
PMCID: PMC3499586
NLM abbreviation: PLoS Pathog
ISSN: 1553-7366
eISSN: 1553-7374
Grant note: F30 MH074266 / NIMH NIH HHS R01 GM082892 / NIGMS NIH HHS MH074266 / NIMH NIH HHS DK091978 / NIDDK NIH HHS GM082892 / NIGMS NIH HHS F30 DK091978 / NIDDK NIH HHS
Language: English
Date published: 2012
Academic Unit: Pathology
Record Identifier: 9984200018302771

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