Key Laboratory of Animal Models and Human Disease Mechanisms of The Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China.
Commun Biol. 2019 Feb 11;2:59. doi: 10.1038/s42003-019-0304-y. eCollection 2019.
Bacterial pore-forming toxin aerolysin-like proteins (ALPs) are widely distributed in animals and plants. However, functional studies on these ALPs remain in their infancy. βγ-CAT is the first example of a secreted pore-forming protein that functions to modulate the endolysosome pathway via endocytosis and pore formation on endolysosomes. However, the specific cell surface molecules mediating the action of βγ-CAT remain elusive. Here, the actions of βγ-CAT were largely attenuated by either addition or elimination of acidic glycosphingolipids (AGSLs). Further study revealed that the ALP and trefoil factor (TFF) subunits of βγ-CAT bind to gangliosides and sulfatides, respectively. Additionally, disruption of lipid rafts largely impaired the actions of βγ-CAT. Finally, the ability of βγ-CAT to clear pathogens was attenuated in AGSL-eliminated frogs. These findings revealed a previously unknown double binding pattern of an animal-secreted ALP in complex with TFF that initiates ALP-induced endolysosomal pathway regulation, ultimately leading to effective antimicrobial responses.
细菌孔形成毒素 aerolysin 样蛋白 (ALPs) 在动植物中广泛分布。然而，这些 ALPs 的功能研究仍处于起步阶段。βγ-CAT 是第一个通过内吞作用和形成内体溶酶体孔来调节内体溶酶体途径的分泌孔形成蛋白的例子。然而，介导 βγ-CAT 作用的特定细胞表面分子仍不清楚。在这里，βγ-CAT 的作用通过添加或消除酸性糖脂 (AGSL) 而大大减弱。进一步的研究表明，βγ-CAT 的 ALP 和三叶因子 (TFF) 亚基分别与神经节苷脂和硫酸脑苷脂结合。此外，脂筏的破坏在很大程度上削弱了 βγ-CAT 的作用。最后，在消除 AGSL 的青蛙中，βγ-CAT 清除病原体的能力减弱。这些发现揭示了一种动物分泌的 ALP 与 TFF 结合的先前未知的双重结合模式，该模式启动了 ALP 诱导的内体溶酶体途径调节，最终导致有效的抗菌反应。
