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

Miwa Sasai; Naoya Sakaguchi; Ji Su Ma; Shuhei Nakamura; Tsuyoshi Kawabata; Hironori Bando; Youngae Lee; Tatsuya Saitoh; Shizuo Akira; Akiko Iwasaki; Daron M Standley; Tamotsu Yoshimori; Masahiro Yamamoto

doi:10.1038/ni.3767

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

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

Authors

Miwa Sasai^{1

2}, Naoya Sakaguchi^{1

2}, Ji Su Ma¹, Shuhei Nakamura^{3

4}, Tsuyoshi Kawabata^{3

4}, Hironori Bando¹, Youngae Lee², Tatsuya Saitoh^{5

6

7}, Shizuo Akira^{5

6}, Akiko Iwasaki⁸, Daron M Standley^{9

10}, Tamotsu Yoshimori^{3

4}, Masahiro Yamamoto^{1

2}

Affiliations

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.

PMID: 28604719
DOI: 10.1038/ni.3767

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.

MeSH terms

ADP-Ribosylation Factor 1 / immunology*
ADP-Ribosylation Factor 1 / metabolism
Animals
Apoptosis Regulatory Proteins
Autophagy / immunology*
Autophagy-Related Protein 8 Family
CRISPR-Cas Systems
Carrier Proteins / immunology*
Carrier Proteins / metabolism
Computer Simulation
Cytoskeletal Proteins / immunology
Cytoskeletal Proteins / metabolism
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Fluorescent Antibody Technique
GTP Phosphohydrolases / immunology
GTP Phosphohydrolases / metabolism
Gene Editing
Immunoblotting
Immunoprecipitation
Interferon-gamma / immunology*
Interferon-gamma / metabolism
Intracellular Signaling Peptides and Proteins
Membrane Proteins / immunology
Membrane Proteins / metabolism
Mice
Microtubule-Associated Proteins / immunology*
Microtubule-Associated Proteins / metabolism
Toxoplasma / immunology*
Toxoplasmosis / immunology*

Substances

Apoptosis Regulatory Proteins
Autophagy-Related Protein 8 Family
Carrier Proteins
Cytoskeletal Proteins
GABARAP protein, mouse
Gabarapl1 protein, mouse
Gabarapl2 protein, mouse
Intracellular Signaling Peptides and Proteins
Map1lc3b protein, mouse
Membrane Proteins
Microtubule-Associated Proteins
Interferon-gamma
GTP Phosphohydrolases
ADP-Ribosylation Factor 1