Henan University of Science and Technology, College of Animal Science and Technology, 263 Kaiyuan Ave, Luoyang, 471023, China.
Northwest Agriculture and Forestry University, College of Veterinary Medicine, Yangling, Shaanxi, 712100, China.
Chem Biol Interact. 2023 Sep 1;382:110629. doi: 10.1016/j.cbi.2023.110629. Epub 2023 Jul 11.
Swainsonine (SW) is the primary toxin in locoweed, a poisonous plant. SW can cause animal poisoning, affect the quality and safety of meat products and threaten human health, but the mechanism of its toxicity is little defined. Here, we identified 159 differentially expressed proteins, many of which are involved in autophagy and glycosylation modification processes, using proteomics sequencing analysis. O-linked-N-acetylglucosamylation (O-GlcNAcylation) is a glycosylation modification widely involved in various biological processes. Our results show that SW toxicity is related to O-GlcNAcylation. In addition, increased O-GlcNAcylation with the O-GlcNAcase (OGA) inhibitor TMG promoted autophagy, while decreased O-GlcNAcylation with the O-GlcNAc transferase (OGT) inhibitor OSMI inhibited autophagy. Further analysis by Immunoprecipitation (IP) showed that SW could change the O-GlcNAcylation of Cathepsin D (CTSD), reducing the expression of mature CTSD (m-CTSD). In summary, these findings suggest that SW inhibits the O-GlcNAcylation of CTSD, affecting its maturation and leading to the impairment of lysosome function. Consequently, it inhibits autophagy degradation, and causes cytotoxicity, providing a new theoretical basis for SW toxicological mechanism.
苦马豆素（SW）是毒草中的主要毒素。SW 可引起动物中毒，影响肉产品的质量和安全，威胁人类健康，但对其毒性的机制知之甚少。在这里，我们使用蛋白质组学测序分析鉴定了 159 种差异表达蛋白，其中许多与自噬和糖基化修饰过程有关。O-连接的 N-乙酰氨基葡萄糖（O-GlcNAcylation）是一种广泛参与各种生物过程的糖基化修饰。我们的结果表明，SW 毒性与 O-GlcNAcylation 有关。此外，用 O-GlcNAcase（OGA）抑制剂 TMG 增加 O-GlcNAcylation 会促进自噬，而用 O-GlcNAc 转移酶（OGT）抑制剂 OSMI 减少 O-GlcNAcylation 会抑制自噬。通过免疫沉淀（IP）进一步分析表明，SW 可以改变组织蛋白酶 D（CTSD）的 O-GlcNAcylation，降低成熟 CTSD（m-CTSD）的表达。综上所述，这些发现表明，SW 抑制 CTSD 的 O-GlcNAcylation，影响其成熟并导致溶酶体功能受损。因此，它抑制自噬降解，并导致细胞毒性，为 SW 毒理学机制提供了新的理论依据。
