刺
干扰素基因刺激剂
泛素连接酶
蛋白酶体
兴奋剂
先天免疫系统
泛素
癌症研究
医学
细胞生物学
免疫学
生物
受体
免疫系统
内科学
工程类
基因
遗传学
航空航天工程
作者
Zhen-Gang Zhu,Rebecca L. Johnson,Zhigang Zhang,Laura E. Herring,Guochun Jiang,Blossom Damania,Lindsey I. James,Pengda Liu
出处
期刊:Research Square - Research Square
日期:2023-03-22
标识
DOI:10.21203/rs.3.rs-2496673/v1
摘要
Abstract STING acts as a cytosolic nucleotide sensor to trigger host defense upon viral or bacterial infection. While STING hyperactivation can exert anti-tumor effects by increasing T-cell filtrates, in other contexts hyperactivation of STING can contribute to autoimmune and neuroinflammatory diseases. Several STING targeting agonists and a smaller subset of antagonists have been developed, yet STING targeted degraders, or PROTACs, remain underexplored. Here, we report a series of STING-agonist derived PROTACs that promote STING degradation in renal cell carcinoma (RCC) cells. We show that our STING PROTACs activate STING and target activated/phospho-STING for degradation. Locking STING on the endoplasmic reticulum via site-directed mutagenesis disables STING translocation to the proteasome and resultingly blocks STING degradation. We also demonstrate that PROTAC treatment blocks downstream signaling events and attenuates the anti-viral response. Interestingly, we find that VHL acts as a bona fide E3 ligase for STING in RCC; thus, VHL-recruiting STING PROTACs further promote VHL-dependent STING degradation. Our study reveals the design and biological assessment of VHL-recruiting agonist-derived STING PROTACs, as well as demonstrates an example of hijacking a physiological E3 ligase to enhance target protein degradation.
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