GMS proteins shield endocellular membranes from accumulation of effector Immunity-Related GTPases
Jelena Maric-Biresev
Immunity-related GTPases (IRGs) play an important role in host immune response to a variety of intracellular pathogens by accumulation at the membranes of the pathogens and their disruption. However, it was never understood how exactly IRG proteins distinguish the membranes of the pathogen from the host membranes.
Previously, it has been reported that regulatory IRG proteins, named GMS proteins, keep the effector IRG proteins, named GKS proteins, in the inactive GDP-bound state. In this study, it has been shown that GMS proteins also play an important role in protection of the endocellular compartments from GKS protein off-target activation. In the absence of the GMS protein Irgm1, which is localized at the lysosomes, GKS proteins Irga6, Irgb6, Irgb10 and Irgd accumulate and activate at these organelles. In the absence of Irgm3, a GMS protein which is localized at the endoplasmic reticulum (ER), GKS protein Irga6 accumulates at the ER. However, in the cells that lack Irgm1 and Irgm3, GKS proteins accumulate only to lipid droplets, but not to lysosomes or ER, indicating that GKS structures do not accumulate at every GMS-free membrane.
In the second part of the study, the consequences Irgm1 accumulation to the lysosomes are investigated. Irgm1 KO mice undergo leukopenia and succumb after a variety of infections and inflammatory states. The results of this study suggest that the failure of Irgm1 KO mice is rather an indirect consequence of the off-target action of the GKS proteins, than the direct consequence of the Irgm1 response to a variety of pathogens. The GKS proteins, that accumulate at the lysosomes in Irgm1 KO cells, affect the acidity of these organelles and therefore lysosomal ability to process autophagosomes. In IFNγ-induced Irgm1 KO mouse embryonic fibroblasts (MEFs) the mature autophagosome marker LC3-II level is enhanced, the number of autophagosomes is increased and the co-localization between autophagosomes and lysosomes is higher than in the non-induced cells.
Therefore, in this study, it is proposed that the autophagic flux of IFNγ-induced Irgm1 KO MEFs is impaired. The lymphocytes of the Irgm1 KO mice, that are stimulated to proliferate as a response to infection, could be the cells that are most affected by autophagic flux arrest and lysosomal acidification impairment. Thus, this effect could be the cause of described defects in lymphocyte proliferation and lymphocyte necrosis, which cause the death of the Irgm1 KO mous
