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Nat Immunol. 2017 Aug;18(8):899-910. doi: 10.1038/ni.3767. Epub 2017 Jun 12.

Essential role for GABARAP autophagy proteins in interferon-inducible GTPase-mediated host defense.

Author information

1
Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
2
Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
3
Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
4
Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
6
Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
7
Division of Inflammation Biology, Institute for Enzyme Research, Tokushima University, Tokushima, Japan.
8
Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
9
Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
10
Laboratory of System Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.

Abstract

Mammalian autophagy-related 8 (Atg8) homologs consist of LC3 proteins and GABARAPs, all of which are known to be involved in canonical autophagy. In contrast, the roles of Atg8 homologs in noncanonical autophagic processes are not fully understood. Here we show a unique role of GABARAPs, in particular gamma-aminobutyric acid (GABA)-A-receptor-associated protein-like 2 (Gabarapl2; also known as Gate-16), in interferon-γ (IFN-γ)-mediated antimicrobial responses. Cells that lacked GABARAPs but not LC3 proteins and mice that lacked Gate-16 alone were defective in the IFN-γ-induced clearance of vacuolar pathogens such as Toxoplasma. Gate-16 but not LC3b specifically associated with the small GTPase ADP-ribosylation factor 1 (Arf1) to mediate uniform distribution of interferon-inducible GTPases. The lack of GABARAPs reduced Arf1 activation, which led to formation of interferon-inducible GTPase-containing aggregates and hampered recruitment of interferon-inducible GTPases to vacuolar pathogens. Thus, GABARAPs are uniquely required for antimicrobial host defense through cytosolic distribution of interferon-inducible GTPases.

PMID:
28604719
DOI:
10.1038/ni.3767
[Indexed for MEDLINE]

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