Wan Xueqi, Zhang Huan, Tian Jinfan, Liu Libo, An Ziyu, Zhao Xin, Zhang Lijun, Yang Xueyao, Ge Changjiang, Song Xiantao
Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China.
Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing 100029, P.R. China.
Int J Biol Sci. 2024 Oct 28;20(15):5868-5887. doi: 10.7150/ijbs.101247. eCollection 2024.
Over the past several decades, a canonical pathway called the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) mediating type I interferon (IFN) release via TANK-binding kinase 1(TBK1) / IFN regulatory factor 3 (IRF3) pathway has been widely investigated and characterized. Unexpectedly, recent studies show that the cGAS-STING noncanonically activates the protein kinase RNA-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α), an essential branch of unfolded protein response (UPR), even before the activation of the TBK1/IRF3 signaling. Additionally, we found that the PERK could regulate the STING signaling besides being modulated by upstream cGAS-STING. However, earlier evidence solely focused on the unidirectional regulation of STING and PERK, lacking their functional crosstalk. Hence, we postulate that there is a complex relationship between the cGAS-STING and PERK-eIF2α pathways and that, through convergent downstream signaling, they may collaboratively contribute to the pathophysiology of cardiovascular diseases (CVDs) via the cGAS-STING/PERK-eIF2α signaling axis. This study provides a novel pathway for the development of CVDs and paves the foundation for potential therapeutic targets for CVDs.
在过去几十年中，一种名为环鸟苷酸-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）的经典途径通过TANK结合激酶1（TBK1）/干扰素调节因子3（IRF3）途径介导I型干扰素（IFN）释放，该途径已得到广泛研究和表征。出乎意料的是，最近的研究表明，cGAS-STING甚至在TBK1/IRF3信号激活之前就非经典地激活了蛋白激酶RNA样内质网激酶（PERK）-真核起始因子2α（eIF2α），这是未折叠蛋白反应（UPR）的一个重要分支。此外，我们发现PERK除了受上游cGAS-STING调节外，还可以调节STING信号。然而，早期证据仅关注STING和PERK的单向调节，缺乏它们的功能相互作用。因此，我们推测cGAS-STING和PERK-eIF2α途径之间存在复杂关系，并且通过汇聚的下游信号，它们可能通过cGAS-STING/PERK-eIF2α信号轴协同促进心血管疾病（CVD）的病理生理学。本研究为CVD的发展提供了一条新途径，并为CVD潜在治疗靶点奠定了基础。
