Mechanisms Regulating the Positioning of Mouse p47 Resistance GTPases LRG-47 and IIGP1 on Cellular Membranes: Retargeting to Plasma Membrane Induced by Phagocytosis

Martens, Sascha; Sabel, Katja; Lange, Rita; Uthaiah, Revathy C.; Wolf, Eva; Howard, Jonathan

doi:10.4049/jimmunol.173.4.2594

Cited by 109 publications

(238 citation statements)

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“…Immunoreagents used in this study were 3E2 mouse monoclonal antibody against ROP5 isoforms (Leriche and Dubremetz, 1991), anti‐ROP18 rat antiserum (El Hajj and Dubremetz, unpublished), affinity‐purified rabbit sera 87558 against (pT108)Irga6 (Steinfeldt et al ., 2010), 10D7 and 10E7 mouse monoclonal antibodies (Papic et al ., 2008) or 165 rabbit antiserum (Martens et al ., 2004) against Irga6, B34 mouse monoclonal antibody (Carlow et al ., 1998) against Irgb6, 940/6 rabbit antiserum (unpublished) against Irgb10, 2078 rabbit antiserum (Martens et al ., 2004) against Irgd, 3.1.2 and 2.4.21 rat monoclonal antibodies against T. gondii GRA7 (unpublished), and rabbit anti‐calnexin antiserum (Calbiochem).…”

Section: Methodsmentioning

confidence: 99%

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

Hermanns

Müller

Könen‐Waisman

et al. 2015

Cellular Microbiology

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SummaryIn mice, avirulent strains (e.g. types II and III) of the protozoan parasite Toxoplasma gondii are restricted by the immunity‐related GTPase (IRG) resistance system. Loading of IRG proteins onto the parasitophorous vacuolar membrane (PVM) is required for vacuolar rupture resulting in parasite clearance. In virulent strain (e.g. type I) infections, polymorphic effector proteins ROP5 and ROP18 cooperate to phosphorylate and thereby inactivate mouse IRG proteins to preserve PVM integrity. In this study, we confirmed the dense granule protein GRA7 as an additional component of the ROP5/ROP18 kinase complex and identified GRA7 association with the PVM by direct binding to ROP5. The absence of GRA7 results in reduced phosphorylation of Irga6 correlated with increased vacuolar IRG protein amounts and attenuated virulence. Earlier work identified additional IRG proteins as targets of T. gondii ROP18 kinase. We show that the only specific target of ROP18 among IRG proteins is in fact Irga6. Similarly, we demonstrate that GRA7 is strictly an Irga6‐specific virulence effector. This identifies T. gondii GRA7 as a regulator for ROP18‐specific inactivation of Irga6. The structural diversity of the IRG proteins implies that certain family members constitute additional specific targets for other yet unknown T. gondii virulence effectors.

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Section: Methodsmentioning

confidence: 99%

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

Hermanns

Müller

Könen‐Waisman

et al. 2015

Cellular Microbiology

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“…The reduced citrate availability would probably have the effect of decreasing fatty acid synthesis as well as promoting glycolysis by reducing the inhibitory effect of citrate on phosphofructokinase (85). It is plausible that Irgm1 could play a direct role in lipid homeostasis, because it is a dynamin-like GTPase that associates with specific intracellular membrane compartments, including the Golgi, where it may alter membrane trafficking (11,12,21,25,52,78,87). Additionally, IRGM proteins have been reported to play roles in lipid droplet maintenance (27,78,88).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Schmidt

Fee

Henry

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-␥ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found that uninfected Irgm1-deficient mice displayed high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-␥-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1 deficiency drives metabolic dysfunction in macrophages in a manner that is cell-autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.

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“…Thus, nucleotide binding by hGBP-1 is required, consistent with the hypothesis that the Golgi is the target membrane for the GTP-bound form. Two members of the p47 GTPase family, IIGP1 and LRG-47, are also associated with the Golgi but in a constitutive manner (45). Redistribution of LRG-47 to the plasma membrane and phagosomes follows phagocytosis and may be responsible for promoting its antimicrobial function.…”

Section: Discussionmentioning

confidence: 99%

Golgi targeting of human guanylate-binding protein-1 requires nucleotide binding, isoprenylation, and an IFN-γ-inducible cofactor

Modiano

Cresswell

2005

Proc. Natl. Acad. Sci. U.S.A.

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Human guanylate-binding protein-1 (hGBP-1) is a large GTPase, similar in structure to the dynamins. Like many smaller GTPases of the Ras͞Rab family, it is farnesylated, suggesting it may dock into membranes and perhaps play a role in intracellular trafficking. To date, however, hGBP-1 has never been associated with a specific intracellular compartment. Here we present evidence that hGBP-1 can associate with the Golgi apparatus. Redistribution from the cytosol to the Golgi was observed by immunofluorescence and subcellular fractionation after aluminum fluoride treatment, suggesting that it occurs when hGBP-1 is in its GTP-bound state. Relocalization was blocked by a farnesyl transferase inhibitor. The C589S mutant of hGBP-1, which cannot be farnesylated, and the previously uncharacterized R48P mutant, which cannot bind GTP, both failed to localize to the Golgi. These two mutants had a dominant-negative effect, preventing endogenous wild-type hGBP-1 from efficiently redistributing after aluminum fluoride treatment. Furthermore, hGBP-1 requires another IFN-␥-induced factor to be targeted to the Golgi, because constitutively expressed hGBP-1 remained cytosolic in cells treated with aluminum fluoride unless the cells were preincubated with IFN-␥. Finally, two nonhydrolyzing mutants of hGBP-1, corresponding to active mutants of Ras family proteins, failed to constitutively associate with the Golgi; we propose three possible explanations for this surprising result.antiviral proteins ͉ GTPases ͉ innate immunity

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Mechanisms Regulating the Positioning of Mouse p47 Resistance GTPases LRG-47 and IIGP1 on Cellular Membranes: Retargeting to Plasma Membrane Induced by Phagocytosis

Cited by 109 publications

References 33 publications

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

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

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Golgi targeting of human guanylate-binding protein-1 requires nucleotide binding, isoprenylation, and an IFN-γ-inducible cofactor

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