Universität zu Köln

Maric-Biresev, Jelena, Hunn, Julia P., Krut, Oleg, Helms, J. Bernd, Martens, Sascha and Howard, Jonathan C. (2016). Loss of the interferon-gamma-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 mice to infection. BMC Biol., 14. LONDON: BMC. ISSN 1741-7007

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Abstract

Background: The interferon-gamma (IFN-gamma)-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. Results: We 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-gamma, 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. Conclusions: The 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Maric-Biresev, Jelena UNSPECIFIED UNSPECIFIED UNSPECIFIED Hunn, Julia P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krut, Oleg UNSPECIFIED UNSPECIFIED UNSPECIFIED Helms, J. Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Martens, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Howard, Jonathan C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-278404
DOI:	10.1186/s12915-016-0255-4
Journal or Publication Title:	BMC Biol.
Volume:	14
Date:	2016
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1741-7007
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; RESISTANCE GTPASES; TOXOPLASMA-GONDII; P47 GTPASES; CELLULAR-RESPONSE; HOST-RESISTANCE; LRG-47; AUTOPHAGY; MECHANISM; MEMBRANE Multiple languages Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27840