Localisation and mislocalisation of the interferon-inducible immunity-related GTPase, Irgm1 (LRG-47) in mouse cells

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2010

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Abstract

Irgm1 (LRG-47) is an interferon-inducible Golgi membrane associated GTPase of the mouse whose disruption causes susceptibility to many different intracellular pathogens. Irgm1 has been variously interpreted as a regulator of homologous effector GTPases of the IRG family, a regulator of phagosome maturation and as an initiator of autophagy in interferoninduced cells. We find that endogenous Irgm1 localises to late endosomal and lysosomal compartments in addition to the Golgi membranes. The targeting motif known to be required for Golgi localisation is surprisingly also required for endolysosomal localisation. However, unlike Golgi localisation, localisation to the endolysosomal system also requires the functional integrity of the nucleotide binding site, and thus probably reflects transient activation. Golgi localisation is lost when Irgm1 is tagged at either N- or C-termini with EGFP, while localisation to the endolysosomal system is relatively favoured. N-terminally tagged Irgm1 localises predominantly to early endosomes, while C-terminally tagged Irgm1 localises to late endosomes and lysosomes. Both these anomalous distributions are reversed by inactivation of the nucleotide binding site, and the tagged proteins both revert to Golgi membrane localisation. Irgm1 is the first IRG protein to be found associated with the endolysosomal membrane system in addition to either Golgi (Irgm1 and Irgm2) or ER (Irgm3) membranes, and we interpret the result to be in favour of a regulatory function of IRGM proteins at cellular membrane systems. In future analyses it should be borne in mind that tagging of Irgm1 leads to loss of Golgi localisation and enhanced localisation on endolysosomal membranes, probably as a result of constitutive activation. © 2010 Zhao et al.

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10.1371/journal.pone.0008648

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Zhao, Yang O, Stephanie Könen-Waisman, Gregory A Taylor, Sascha Martens and Jonathan C Howard (2010). Localisation and mislocalisation of the interferon-inducible immunity-related GTPase, Irgm1 (LRG-47) in mouse cells. PLoS ONE, 5(1). p. e8648. 10.1371/journal.pone.0008648 Retrieved from https://hdl.handle.net/10161/4519.

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Taylor

Gregory Alan Taylor

Professor in Medicine

My lab uses mouse genetic modeling and molecular and cellular techniques to study basic biochemical pathways of relevance to aging biology.

I. Aging is often accompanied by increases in inflammation. A major interest of the lab is how perturbations in the regulation of autophagy and mitochondrial dynamics in cells are linked to inflammation. One project in the lab focuses on a family of interferon-gamma and LPS regulated proteins, the Immunity Related GTPases (IRGs). The lab has shown that mice and cells lacking one of these proteins, Irgm1, have excessive inflammatory responses that are accompanied by decreases in autophagy and mitophagy, and altered cellular metabolism. IRG genes in human (IRGM) have been linked to several inflammatory diseases including Crohn’s disease and sepsis. Current work in the lab focuses on their role in those diseases using bacterial and relevant mouse models.

II. Altered expression of the cytokine Transforming Growth Factor beta (TGF-b) has been linked with a number of aging processes, including stem cell and neural function. TGF-b is consequently a therapeutic target for a number of age-related diseases. The lab is studying a novel regulator of TGF-b expression called P311, which drives TGF-b translation. Mice have been created that lack P311 and are being used to address the role of P311 in a number of physiological processes.


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