Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Parasitol Int. 2021 Aug;83:102335. doi: 10.1016/j.parint.2021.102335. Epub 2021 Mar 23.
Sporozoites of the etiological agent of malaria, Plasmodium, form parasitophorous vacuoles (PVs) in hepatocytes. The PV membranes (PVM) are coated with a well-known host autophagy marker LC3 and parasite-derived protein called Upregulated in infective sporozoites 3 (UIS3), which has been shown to interact with LC3 and inhibit LC3-mediated autophagic disruption at the PV. Although uis3(-) sporozoites cannot proliferate in wild-type cells, they can replicate efficiently in cells defective in autophagy due to the lack of Atg proteins such as Atg3, Atg5 and Atg7, since these Atg proteins are essential for processing of LC3. However, it remains to be seen whether other Atg proteins participate in the restriction of uis3(-) parasite growth. Here we show that, despite essential roles of Atg9 and Atg14 in autophagy, both proteins are dispensable for the restriction of uis3(-) parasite growth. Moreover, we found that cells lacking LC3 proteins are also able to restrict uis3(-) parasite growth. In sharp contrast, GABARAPs, another subfamily of mammalian Atg8, participated in suppression of uis3(-) parasite growth. Taken together, contrary to a previous model in which UIS3 avoids host LC3- and autophagy-dependent parasite elimination program, our data demonstrate a role of GABARAPs for suppression of uis3(-) parasite growth in a manner independent on autophagy.
疟原虫的病原孢子形成寄生空泡（PVs）在肝细胞中。PV 膜（PVM）被一种著名的宿主自噬标记物 LC3 和一种叫做感染性孢子上调 3（UIS3）的寄生虫衍生蛋白所覆盖，已经证明 UIS3 与 LC3 相互作用，并抑制 PV 中的 LC3 介导的自噬破坏。虽然 uis3(-)孢子在野生型细胞中不能增殖，但由于缺乏 Atg 蛋白，如 Atg3、Atg5 和 Atg7，它们可以在自噬缺陷的细胞中有效地复制，因为这些 Atg 蛋白是 LC3 加工所必需的。然而，其他 Atg 蛋白是否参与限制 uis3(-)寄生虫的生长仍有待观察。在这里，我们表明，尽管 Atg9 和 Atg14 在自噬中起着至关重要的作用，但这两种蛋白对于限制 uis3(-)寄生虫的生长都是可有可无的。此外，我们发现缺乏 LC3 蛋白的细胞也能够限制 uis3(-)寄生虫的生长。相比之下，GABARAPs，哺乳动物 Atg8 的另一个亚家族，参与抑制 uis3(-)寄生虫的生长。总之，与之前的模型相反，该模型认为 UIS3 避免了宿主 LC3 和自噬依赖性寄生虫消除程序，我们的数据表明 GABARAPs 在不依赖自噬的情况下抑制 uis3(-)寄生虫生长的作用。
