Universität zu Köln

Fentress, Sarah J., Steinfeldt, Tobias, Howard, Jonathan C. and Sibley, L. David (2012). The arginine-rich N-terminal domain of ROP18 is necessary for vacuole targeting and virulence of Toxoplasma gondii. Cell Microbiol., 14 (12). S. 1921 - 1934. HOBOKEN: WILEY. ISSN 1462-5822

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Abstract

Toxoplasma gondii uses specialized secretory organelles called rhoptries to deliver virulence determinants into the host cell during parasite invasion. One such determinant called rhoptry protein 18 (ROP18) is a polymorphic serine/threonine kinase that phosphorylates host targets to modulate acute virulence. Following secretion into the host cell, ROP18 traffics to the parasitophorous vacuole membrane (PVM) where it is tethered to the cytosolic face of this hostpathogen interface. However, the functional consequences of PVM association are not known. In this report, we show that ROP18 mutants altered in an arginine-rich domain upstream of the kinase domain fail to associate to the PVM following secretion from rhoptries. During infection, host cells upregulate immunity-related GTPases that localize to and destroy the PVM surrounding the parasites. ROP18 disarms this host innate immune pathway by phosphorylating IRGs in a critical GTPase domain and preventing loading on the PVM. Vacuole-targeting mutants of ROP18 failed to phosphorylate Irga6 and were unable to divert IRGs from the PVM, despite retaining intrinsic kinase activity. As a consequence, these mutants were avirulent in a mouse model of acute toxoplasmosis. Thus, the association of ROP18 with the PVM, mediated by its N-terminal arginine-rich domain, is critical to its function as a virulence determinant.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fentress, Sarah J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinfeldt, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Howard, Jonathan C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sibley, L. David UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-477690
DOI:	10.1111/cmi.12022
Journal or Publication Title:	Cell Microbiol.
Volume:	14
Number:	12
Page Range:	S. 1921 - 1934
Date:	2012
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1462-5822
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELL PLASMA-MEMBRANE; PARASITOPHOROUS VACUOLE; RHOPTRY PROTEINS; MOVING JUNCTION; INVASION; SECRETION; FAMILY; ASSOCIATION; RESISTANCE; TRAFFICKING Multiple languages Cell Biology; Microbiology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47769