College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, PR China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China.
College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, PR China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China.
Toxicology. 2020 Sep;442:152538. doi: 10.1016/j.tox.2020.152538. Epub 2020 Jul 18.
Cadmium (Cd) is one of worldwide environmental pollutants that causes bone homeostasis, which depends on the resorption of bones by osteoclasts and formation of bones by the osteoblasts (OB). However, the Cd toxicity on OB and its mechanism are unclear. Autophagy is an evolutionarily conserved degradation process in which domestic intracellular components are selectively digested for the recycling of nutrients and energy. This process is indispensable for cell homeostasis maintenance and stress responses. Dysregulation at the level of autophagic activity consequently disturbs the balance between bone formation and bone resorption and mediates the onset and progression of multiple bone diseases, including osteoporosis. TAK1 has been recently emerged as an activator of AMPK and hence an autophagy inducer. AMPK is a key molecule that induces autophagy and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by mTORC1. In this study, we found that Cd treatment caused the formation of autophagosomes, LC3-II lipidation and p62 downregulation, and the increased autophagic flux, indicating that Cd treatment induced autophagy in OBs. Cd treatment induced TAK1 activation mediated AMPK phosphorylation, which promoted autophagy via phosphorylation of ULK1 at S317. Meanwhile, Cd treatment dramatically decreased mTORC1, S6K1, 4E-BP1, S6, ULK1 and ULK1 phosphorylation, suggesting that mTORC1 activity was inhibited and inactive mTORC1 prevents ULK1 activation by phosphorylating ULK1 at SerS555 and Ser757. Our data strongly suggest that TAK1 mediates AMPK activation, which activates ULK1 by phosphorylating ULK1 and suppressing mTORC1-mediated ULK1 and ULK1 phosphorylation. Our study has revealed a signaling mechanism for TAK1 in Cd-induced autophagy in OBs.
镉 (Cd) 是一种全球性的环境污染物，会导致骨稳态失衡，这依赖于破骨细胞对骨骼的吸收和成骨细胞（OB）对骨骼的形成。然而，Cd 对 OB 的毒性及其机制尚不清楚。自噬是一种进化上保守的降解过程，其中细胞内的成分被选择性地消化，以回收营养物质和能量。这个过程对于细胞内稳态的维持和应激反应是必不可少的。自噬活性的失调会破坏骨形成和骨吸收之间的平衡，并介导多种骨疾病的发生和进展，包括骨质疏松症。TAK1 最近被认为是 AMPK 的激活剂，因此也是自噬的诱导剂。AMPK 是一种关键的分子，它可以诱导自噬并调节细胞代谢以维持能量内稳态。相反，mTORC1 抑制自噬。在本研究中，我们发现 Cd 处理导致自噬体的形成、LC3-II 脂质化和 p62 的下调，以及自噬流的增加，表明 Cd 处理诱导了 OB 中的自噬。Cd 处理诱导 TAK1 激活介导 AMPK 磷酸化，通过磷酸化 ULK1 的 S317 促进自噬。同时，Cd 处理显著降低了 mTORC1、S6K1、4E-BP1、S6、ULK1 和 ULK1 的磷酸化，表明 mTORC1 活性被抑制，失活的 mTORC1 通过磷酸化 ULK1 的 SerS555 和 Ser757 来阻止 ULK1 的激活。我们的数据强烈表明，TAK1 介导 AMPK 的激活，通过磷酸化 ULK1 激活 ULK1，并抑制 mTORC1 介导的 ULK1 和 ULK1 磷酸化。本研究揭示了 TAK1 在 Cd 诱导的 OB 自噬中的信号机制。
