The p97 Inhibitor UPCDC-30245 Blocks Endo-Lysosomal Degradation.
The p97 Inhibitor UPCDC-30245 Blocks Endo-Lysosomal Degradation.
复制标题
DOI：
10.3390/ph15020204
复制
发表时间：
2022-02-07
期刊：
影响因子：
--
通讯作者：
Chou TF
中科院分区：
文献类型：
--
作者：
Wang F;Li S;Cheng KW;Rosencrans WM;Chou TF
小分子抑制剂的不同作用模式为研究基础生物学和开发治疗方法提供了多功能工具。然而，评估其确切的作用机制仍然是一项具有挑战性的任务。我们确定了两类p97 ATP酶抑制剂：ATP竞争性和变构性。我们发现，变构p97抑制剂UPCDC-30245不影响p97的两种众所周知的细胞功能，内质网相关蛋白降解和未折叠蛋白反应途径;相反，它强烈增加了微管相关蛋白1A/1B轻链3B（LC 3-II）的脂化形式，表明自噬途径的改变。为了评估分子机制，我们对UPCDC-30245处理的细胞进行蛋白质组学分析。我们的结果显示，UPCDC-30245通过抑制早期内体的形成和降低溶酶体的酸度来阻断内-溶酶体降解，这是用有效的p97抑制剂CB-5083未观察到的效果。这种独特的作用使我们能够证明UPCDC-30245通过阻断病毒进入而对冠状病毒表现出抗病毒作用。
The diverse modes of action of small molecule inhibitors provide versatile tools to investigate basic biology and develop therapeutics. However, it remains a challenging task to evaluate their exact mechanisms of action. We identified two classes of inhibitors for the p97 ATPase: ATP competitive and allosteric. We showed that the allosteric p97 inhibitor, UPCDC-30245, does not affect two well-known cellular functions of p97, endoplasmic-reticulum-associated protein degradation and the unfolded protein response pathway; instead, it strongly increases the lipidated form of microtubule-associated proteins 1A/1B light chain 3B (LC3-II), suggesting an alteration of autophagic pathways. To evaluate the molecular mechanism, we performed proteomic analysis of UPCDC-30245 treated cells. Our results revealed that UPCDC-30245 blocks endo-lysosomal degradation by inhibiting the formation of early endosome and reducing the acidity of the lysosome, an effect not observed with the potent p97 inhibitor CB-5083. This unique effect allows us to demonstrate UPCDC-30245 exhibits antiviral effects against coronavirus by blocking viral entry.
登录
查看更多内容
影响因子：
3.4
作者：
Fang, Chen-Jie;Gui, Lin;Zhang, Xiaoyi;Moen, Derek R.;Li, Kelin;Frankowski, Kevin J.;Lin, Henry J.;Schoenen, Frank J.;Chou, Tsui-Fen
通讯作者：
Chou, Tsui-Fen
影响因子：
7.6
作者：
Brown, Ariane J.;Won, John J.;Sheahan, Timothy P.
通讯作者：
Sheahan, Timothy P.
DOI：
10.1073/pnas.1416660111
发表时间：
2014-10-14
影响因子：
11.1
作者：
Kan, Shih-hsin;Aoyagi-Scharber, Mika;Neufeld, Elizabeth F.
通讯作者：
Neufeld, Elizabeth F.
影响因子：
4.4
作者：
Gaetani, Massimiliano;Sabatier, Pierre;Zubarev, Roman A.
通讯作者：
Zubarev, Roman A.
影响因子：
4.9
作者：
Keyaerts, Els;Li, Sandra;Maes, Piet
通讯作者：
Maes, Piet