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2017-6-13

Although functions of autophagy-related (Atg) proteins in canonical autophagy are well understood, recent studies have revealed roles of Atg proteins in various other biological processes. While many of Atg genes are highly conserved throughout evolution, the Atg8 gene has undergone expansion in the genome of higher eukaryotes. Mammalian Atg8 homologues consist of LC3s and GABARAPs, all of which are well known to be involved in canonical autophagy. In contrast, the roles of Atg8 homologue member in non-canonical processes are not fully understood. Here we show a unique role of GABARAPs, in particular Gate-16, in  interferon-γ (IFN-γ)-mediated antimicrobial response.

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.

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Figure 1. EM micrograph for Toxisoplasma gondi in Pathogen Containing Bacuole

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Figure 2. GBP is distributed in the cytoplasm in the wt cells. In contrast, GBP is found accumulated in Gate-16 KO cells

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Figure 3. Gate-16 enhances IFN-g-mediated cell autonomous immunity

To learn more about this research, please view the full research report entitled "Essential role for GABARAP autophagy proteins in interferon-inducible GTPase-mediated host defense" at this page of the Nature Immunology website.


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