A Toxoplasma gondii Pseudokinase Inhibits Host IRG Resistance Proteins

Abstract

A secreted kinase from the parasitic protozoan, Toxoplasma gondii , is shown to cooperate with a phylogenetically related pseudokinase to phosphorylate and inactivate a mouse resistance protein of the IRG system.

TheToxoplasma gondiirhoptry protein ROP18 is an Irga6‐specific kinase and regulated by the dense granule protein GRA7

“…1 indicate either that the interaction between Irga6 and GRA7 is indirect and mediated by ROP5 or that direct binding of GRA7 to Irga6 requires a conformational change of the GTPase induced by direct binding of ROP5 (Fleckenstein et al ., 2012). …”

“…4B). These results clearly indicate that GRA7 is an important component within the T. gondii kinase complex, contributing to phosphorylation of Irga6 by ROP5 and ROP18 (Fentress et al ., 2010; Steinfeldt et al ., 2010; Fleckenstein et al ., 2012). …”

“…Certain T. gondii avirulent type II strains also express a virulent allelic form of ROP18 (Saeij et al ., 2006; Niedelman et al ., 2012) but fail to restrict IRG protein accumulation at the PVM to an extent that allows survival in infected mouse cells (Zhao et al ., 2009b). We could demonstrate that for efficient phosphorylation, IRG proteins have to be kept in the inactive GDP‐bound conformation (Fleckenstein et al ., 2012). This conformation is facilitated by direct binding of the pseudokinase ROP5 to IRG proteins (Fleckenstein et al ., 2012; Niedelman et al ., 2012).…”

“…We could demonstrate that for efficient phosphorylation, IRG proteins have to be kept in the inactive GDP‐bound conformation (Fleckenstein et al ., 2012). This conformation is facilitated by direct binding of the pseudokinase ROP5 to IRG proteins (Fleckenstein et al ., 2012; Niedelman et al ., 2012). Although not apparent for an IRG‐specific function of ROP5 in our own experiments (Fleckenstein et al ., 2012), an interaction of ROP5 with ROP18 was reported to control T. gondii virulence by up‐regulation of ROP18 activity (Behnke et al ., 2012).…”

“…This conformation is facilitated by direct binding of the pseudokinase ROP5 to IRG proteins (Fleckenstein et al ., 2012; Niedelman et al ., 2012). Although not apparent for an IRG‐specific function of ROP5 in our own experiments (Fleckenstein et al ., 2012), an interaction of ROP5 with ROP18 was reported to control T. gondii virulence by up‐regulation of ROP18 activity (Behnke et al ., 2012). The rop5 locus is represented by a cluster of tandemly repeated genes encoding three different ROP5 isoforms, ROP5A, ROP5B and ROP5C, each containing multiple copies, and all isoforms are predicted to be catalytically inactive (El Hajj et al ., 2006; Reese and Boothroyd, 2011).…”