IRG and GBP Host Resistance Factors Target Aberrant, “Non-self” Vacuoles Characterized by the Missing of “Self” IRGM Proteins

Arun K Haldar,Raphael H Valdivia,Gregory A Taylor,Joe Dan Dunn,Jörn Coers,Stanley C Henry,Hector A Saka,Eva M Frickel,Anthony S Piro,Denise M Monack

doi:10.1371/journal.ppat.1003414

Abstract

Interferon-inducible GTPases of the Immunity Related GTPase (IRG) and Guanylate Binding Protein (GBP) families provide resistance to intracellular pathogenic microbes. IRGs and GBPs stably associate with pathogen-containing vacuoles (PVs) and elicit immune pathways directed at the targeted vacuoles. Targeting of Interferon-inducible GTPases to PVs requires the formation of higher-order protein oligomers, a process negatively regulated by a subclass of IRG proteins called IRGMs. We found that the paralogous IRGM proteins Irgm1 and Irgm3 fail to robustly associate with “non-self” PVs containing either the bacterial pathogen Chlamydia trachomatis or the protozoan pathogen Toxoplasma gondii. Instead, Irgm1 and Irgm3 reside on “self” organelles including lipid droplets (LDs). Whereas IRGM-positive LDs are guarded against the stable association with other IRGs and GBPs, we demonstrate that IRGM-stripped LDs become high affinity binding substrates for IRG and GBP proteins. These data reveal that intracellular immune recognition of organelle-like structures by IRG and GBP proteins is partly dictated by the missing of “self” IRGM proteins from these structures.

Highlights

Many intracellular pathogens including the bacterium C. trachomatis and the protozoa T. gondii co-opt the host cell endomembrane system to enclose themselves inside membranebound vacuoles
The data presented in this study support a model in which Irgm1 and Irgm3 proteins act as ‘‘guard molecules’’ that block GKS and Guanylate Binding Protein (GBP) proteins from stably associating with ‘‘self’’ structures (Figure 11)
On pathogen-containing vacuoles (PVs), guarding Irgm1 and Irgm3 proteins are present at such low levels that GKS and GBP proteins can firmly attach to these unprotected membranes

Summary

Introduction

Many intracellular pathogens including the bacterium C. trachomatis and the protozoa T. gondii co-opt the host cell endomembrane system to enclose themselves inside membranebound vacuoles. Within the confines of these remodeled PVs, microbes acquire nutrients and replicate [1] To combat these pathogens, the mammalian host has evolved a large repertoire of cell-autonomous defense mechanisms that kill or restrain the replication of microbes residing within vacuoles [2,3]. The mammalian host has evolved a large repertoire of cell-autonomous defense mechanisms that kill or restrain the replication of microbes residing within vacuoles [2,3] While these defense mechanisms are effective at targeting foreign or ‘‘non-self’’ vacuoles, they have the potential to cause organelle damage and must be tightly regulated. The specificity of this intracellular targeting event is well documented [3,6], the underlying mechanism is unclear

Methods

Results

Conclusion