Loss of the interferon-γ-inducible regulatory immunity-related GTPase IRG, Irgm1, causes activation of effector IRG proteins on lysosomes, damaging lysosomal function and predicting the dramatic susceptibility of Irgm1-deficient Reportar como inadecuado




Loss of the interferon-γ-inducible regulatory immunity-related GTPase IRG, Irgm1, causes activation of effector IRG proteins on lysosomes, damaging lysosomal function and predicting the dramatic susceptibility of Irgm1-deficient - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Biology

, 14:33

First Online: 20 April 2016Received: 28 January 2016Accepted: 06 April 2016DOI: 10.1186-s12915-016-0255-4

Cite this article as: Maric-Biresev, J., Hunn, J.P., Krut, O. et al. BMC Biol 2016 14: 33. doi:10.1186-s12915-016-0255-4

Abstract

BackgroundThe interferon-γ IFN-γ-inducible immunity-related GTPase IRG, Irgm1, plays an essential role in restraining activation of the IRG pathogen resistance system. However, the loss of Irgm1 in mice also causes a dramatic but unexplained susceptibility phenotype upon infection with a variety of pathogens, including many not normally controlled by the IRG system. This phenotype is associated with lymphopenia, hemopoietic collapse, and death of the mouse.

ResultsWe show that the three regulatory IRG proteins GMS sub-family, including Irgm1, each of which localizes to distinct sets of endocellular membranes, play an important role during the cellular response to IFN-γ, each protecting specific membranes from off-target activation of effector IRG proteins GKS sub-family. In the absence of Irgm1, which is localized mainly at lysosomal and Golgi membranes, activated GKS proteins load onto lysosomes, and are associated with reduced lysosomal acidity and failure to process autophagosomes. Another GMS protein, Irgm3, is localized to endoplasmic reticulum ER membranes; in the Irgm3-deficient mouse, activated GKS proteins are found at the ER. The Irgm3-deficient mouse does not show the drastic phenotype of the Irgm1 mouse. In the Irgm1-Irgm3 double knock-out mouse, activated GKS proteins associate with lipid droplets, but not with lysosomes, and the Irgm1-Irgm3 does not have the generalized immunodeficiency phenotype expected from its Irgm1 deficiency.

ConclusionsThe membrane targeting properties of the three GMS proteins to specific endocellular membranes prevent accumulation of activated GKS protein effectors on the corresponding membranes and thus enable GKS proteins to distinguish organellar cellular membranes from the membranes of pathogen vacuoles. Our data suggest that the generalized lymphomyeloid collapse that occurs in Irgm1 mice upon infection with a variety of pathogens may be due to lysosomal damage caused by off-target activation of GKS proteins on lysosomal membranes and consequent failure of autophagosomal processing.

KeywordsImmunity-related GTPases IRGs Pathogen recognition Irgm1 Irgm3 Lysosomes Autophagy Electronic supplementary materialThe online version of this article doi:10.1186-s12915-016-0255-4 contains supplementary material, which is available to authorized users.

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Autor: Jelena Maric-Biresev - Julia P. Hunn - Oleg Krut - J. Bernd Helms - Sascha Martens - Jonathan C. Howard

Fuente: https://link.springer.com/







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