School of Physical Education, Yunnan Normal University, Kunming 650500, China.
Human Aging Research Institute, School of Life Science, Nanchang University, Jiangxi Key Laboratory of Human Aging, Nanchang 330031, China.
Toxins (Basel). 2023 Mar 3;15(3):191. doi: 10.3390/toxins15030191.
Toxin-like proteins and peptides of skin secretions from amphibians play important physiological and pathological roles in amphibians. βγ-CAT is a Chinese red-belly toad-derived pore-forming toxin-like protein complex that consists of aerolysin domain, crystalline domain, and trefoil factor domain and induces various toxic effects via its membrane perforation process, including membrane binding, oligomerization, and endocytosis. Here, we observed the death of mouse hippocampal neuronal cells induced by βγ-CAT at a concentration of 5 nM. Subsequent studies showed that the death of hippocampal neuronal cells was accompanied by the activation of Gasdermin E and caspase-1, suggesting that βγ-CAT induces the pyroptosis of hippocampal neuronal cells. Further molecular mechanism studies revealed that the pyroptosis induced by βγ-CAT is dependent on the oligomerization and endocytosis of βγ-CAT. It is well known that the damage of hippocampal neuronal cells leads to the cognitive attenuation of animals. The impaired cognitive ability of mice was observed after intraperitoneal injection with 10 μg/kg βγ-CAT in a water maze assay. Taken together, these findings reveal a previously unknown toxicological function of a vertebrate-derived pore-forming toxin-like protein in the nerve system, which triggers the pyroptosis of hippocampal neuronal cells, ultimately leading to hippocampal cognitive attenuation.
皮肤分泌物中的毒素样蛋白和肽在两栖动物中发挥重要的生理和病理作用。βγ-CAT 是一种源自中华蟾蜍的孔形成毒素样蛋白复合物，由 aerolysin 结构域、晶体结构域和三叶因子结构域组成，通过其膜穿孔过程诱导各种毒性作用，包括膜结合、寡聚化和内吞作用。在这里，我们观察到浓度为 5 nM 的 βγ-CAT 诱导小鼠海马神经元细胞死亡。随后的研究表明，海马神经元细胞的死亡伴随着 Gasdermin E 和 caspase-1 的激活，表明 βγ-CAT 诱导海马神经元细胞发生细胞焦亡。进一步的分子机制研究表明，βγ-CAT 诱导的细胞焦亡依赖于 βγ-CAT 的寡聚化和内吞作用。众所周知，海马神经元细胞的损伤导致动物认知能力下降。在水迷宫实验中，腹腔注射 10μg/kg βγ-CAT 后，观察到小鼠认知能力受损。综上所述，这些发现揭示了一种以前未知的脊椎动物来源的孔形成毒素样蛋白在神经系统中的毒理学功能，它触发海马神经元细胞的细胞焦亡，最终导致海马认知能力下降。
