The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS-STING in response to light damage

Journal of Neuroinflammation

Research

Ming Zou¹  Mi Deng²  Xiangcheng Tang³  Xingmiao Liang⁴  Xiangyu Ge⁴  Yizhi Liu⁴  Xingfei Zhu⁴  Qin Ke⁴  Yulin Chen⁴  Yingfeng Zheng⁴  Lili Gong⁴  Yuwen Gan⁴  David Wan-Cheng Li⁴  Wei Liu⁴ 

[1] Peking University International Cancer Institute, Health Science Center, Peking University, Beijing, China;Peking University International Cancer Institute, Health Science Center, Peking University, Beijing, China;Peking University Cancer Hospital and Institute, Peking University, Beijing, China;Shenzhen Key Laboratory of Ophthalmology, Shenzhen Eye Hospital, Jinan University, Shenzhen, China;State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 510060, Guangzhou, Guangdong, China;

关键词: Retinal degeneration;    BET;    Neuroinflammation;    PROTAC;    cGAS-STING;    Microglia/macrophage;   

DOI  :  10.1186/s12974-023-02804-y

 received in 2023-01-15, accepted in 2023-05-11,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundChronic inflammation significantly contributes to photoreceptor death in blinding retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that act as key proinflammatory factors. We recently found the first-generation BET inhibitor JQ1 alleviated sodium iodate-induced retinal degeneration by suppressing cGAS-STING innate immunity. Here, we investigated the effects and mechanism of dBET6, a proteolysis‑targeting chimera (PROTAC) small molecule that selectively degrades BET by the ubiquitin‒proteasome system, in light-induced retinal degeneration.MethodsMice were exposed to bright light to induce retinal degeneration, and the activation of cGAS-STING was determined by RNA-sequencing and molecular biology. Retinal function, morphology, photoreceptor viability and retinal inflammation were examined in the presence and absence of dBET6 treatment.ResultsIntraperitoneal injection of dBET6 led to the rapid degradation of BET protein in the retina without detectable toxicity. dBET6 improved retinal responsiveness and visual acuity after light damage (LD). dBET6 also repressed LD-induced retinal macrophages/microglia activation, Müller cell gliosis, photoreceptor death and retinal degeneration. Analysis of single-cell RNA-sequencing results revealed cGAS-STING components were expressed in retinal microglia. LD led to dramatic activation of the cGAS-STING pathway, whereas dBET6 suppressed LD-induced STING expression in reactive macrophages/microglia and the related inflammatory response.ConclusionsThis study indicates targeted degradation of BET by dBET6 exerts neuroprotective effects by inhibiting cGAS-STING in reactive retinal macrophages/microglia, and is expected to become a new strategy for treatment of retinal degeneration.

【 授权许可】

CC BY   
© The Author(s) 2023

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