Hou Bolin, Huang Haiwen, Li Yueqian, Liang Jingnan, Xi Zhijun, Jiang Xuejun, Liu Ling, Li Erwei
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
Cell Death Discov. 2022 Jul 13;8(1):319. doi: 10.1038/s41420-022-01106-1.
The underlying mechanism by which growth factor receptor-bound protein 2 (Grb2) regulates necroptosis remains unexplored. In the present study, we found that rasfonin, a fungal natural product and an activator of necroptosis, enhanced Grb2 binding to receptor-interacting serine/threonine kinase 1 (RIP1), which plays a critical role in regulating programmed necrosis. Moreover, we observed that SQSTM/p62 (p62), a protein that can form necrosomes with RIP1, increased its interaction with Grb2 upon rasfonin challenge. Although it has been used as an activator of autophagy in our previous study, here we found that a high dose of rasfonin was able to inhibit autophagic process. Inhibition of RIP1 either chemically or genetically reversed the inhibition of rasfonin on autophagy, whereas knockdown of Grb2 markedly reduced rasfonin-induced necrosis. Additionally, we found that the compound failed to upregulate the expression of RIP1 in Grb2-deprived cells. In summary, our data revealed that Grb2 actively participated in rasfonin-induced necroptosis by interacting with the components of necrosome and mediating their expression.
生长因子受体结合蛋白2（Grb2）调节坏死性凋亡的潜在机制仍未得到探索。在本研究中，我们发现雷佛宁，一种真菌天然产物和坏死性凋亡激活剂，增强了Grb2与受体相互作用丝氨酸/苏氨酸激酶1（RIP1）的结合，RIP1在调节程序性坏死中起关键作用。此外，我们观察到SQSTM/p62（p62），一种可与RIP1形成坏死小体的蛋白质，在雷佛宁刺激后增加了其与Grb2的相互作用。虽然在我们之前的研究中它被用作自噬激活剂，但在这里我们发现高剂量的雷佛宁能够抑制自噬过程。化学或基因抑制RIP1可逆转雷佛宁对自噬的抑制作用，而敲低Grb2则显著降低雷佛宁诱导的坏死。此外，我们发现该化合物未能上调Grb2缺失细胞中RIP1的表达。总之，我们的数据表明Grb2通过与坏死小体成分相互作用并介导其表达，积极参与雷佛宁诱导的坏死性凋亡。
