Essential role for GABARAP autophagy proteins in interferon-inducible GTPase-mediated host defense
Essential role for GABARAP autophagy proteins in interferon-inducible GTPase-mediated host defense
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DOI：
10.1038/ni.3767
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发表时间：
2017-08-01
影响因子：
30.5
通讯作者：
Yamamoto, Masahiro
中科院分区：
文献类型：
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作者：
Sasai, Miwa;Sakaguchi, Naoya;Yamamoto, Masahiro
哺乳动物自噬相关8（Atg 8）同源物由LC 3蛋白和GABARAP组成，已知所有这些蛋白都参与典型的自噬。相比之下，Atg 8同源物在非经典自噬过程中的作用尚未完全了解。在这里，我们展示了GABARAPs，特别是γ-氨基丁酸（GABA）-A-受体相关蛋白样2（Gabarap 12;也称为Gate-16）在干扰素-γ（IFN-γ）介导的抗微生物应答中的独特作用。缺乏GABARAPs但不缺乏LC 3蛋白的细胞和单独缺乏Gate-16的小鼠在IFN-γ诱导的空泡病原体如弓形虫的清除中存在缺陷。Gate-16而非LC 3b特异性与小GTP酶ADP-核糖基化因子1（Arf 1）相关，以介导干扰素诱导型GTP酶的均匀分布。GABARAPs的缺乏减少了Arf 1的激活，导致形成干扰素诱导的GTP酶的聚集体，并阻碍了招聘的干扰素诱导的GTP酶的空泡病原体。因此，GABARAP是通过干扰素诱导型GTP酶的胞质分布进行抗微生物宿主防御所独特需要的。
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-gamma (IFN-gamma)-mediated antimicrobial responses. Cells that lacked GABARAPs but not LC3 proteins and mice that lacked Gate-16 alone were defective in the IFN-gamma-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.