Scoles Daniel R, Pulst Stefan M
Department of Neurology, University of Utah, Salt Lake City, UT, United States.
Front Mol Neurosci. 2024 Jul 25;17:1402055. doi: 10.3389/fnmol.2024.1402055. eCollection 2024.
The cGAS-STING innate immunity pathway and the SREBP-activated cholesterol and fatty acid synthesis pathway are abnormally co-regulated in neurodegenerative disease. Activation of STING signaling occurs at the endoplasmic reticulum (ER) membrane with STING anchored by INSIG1 along with SREBP and the sterol-bound SREBP cleavage activating protein (SCAP) when sterols are in abundance. When sterols are low, the INSIG-dependent STING pathway is inactivated and the SREBP-SCAP complex is translocated to the Golgi where SREBP is cleaved and translocated to the nucleus to transactivate genes for cholesterol and fatty acid synthesis. Thus, there is inverse activation of STING vs. SREBP: when innate immunity is active, pathways for cholesterol and fatty acid synthesis are suppressed, and vice versa. The STING pathway is stimulated by foreign viral cytoplasmic nucleic acids interacting with the cyclic GMP-AMP synthase (cGAS) DNA sensor or RIG-I and MDA5 dsRNA sensors, but with neurodegeneration innate immunity is also activated by self-DNAs and double-stranded RNAs that accumulate with neuronal death. Downstream, activated STING recruits TBK1 and stimulates the transactivation of interferon stimulated genes and the autophagy pathway, which are both protective. However, chronic activation of innate immunity contributes to microglia activation, neuroinflammation and autophagy failure leading to neurodegeneration. STING is also a proton channel that when activated stimulates proton exit from STING vesicles leading to cell death. Here we review the salient features of the innate immunity and cholesterol and fatty acid synthesis pathways, observations of abnormal STING and SREBP signaling in neurodegenerative disease, and relevant therapeutic approaches.
环鸟苷酸-腺苷酸合成酶-干扰素基因刺激蛋白（cGAS-STING）天然免疫途径与固醇调节元件结合蛋白（SREBP）激活的胆固醇和脂肪酸合成途径在神经退行性疾病中存在异常协同调节。当固醇丰富时，STING信号在内质网（ER）膜上被激活，STING与SREBP以及固醇结合的SREBP裂解激活蛋白（SCAP）一起被胰岛素诱导基因1（INSIG1）锚定。当固醇水平较低时，INSIG依赖的STING途径失活，SREBP-SCAP复合物转运至高尔基体，在那里SREBP被裂解并转运至细胞核以反式激活胆固醇和脂肪酸合成相关基因。因此，STING与SREBP呈反向激活：当天然免疫激活时，胆固醇和脂肪酸合成途径受到抑制，反之亦然。STING途径由与环鸟苷酸-腺苷酸合成酶（cGAS）DNA传感器或视黄酸诱导基因I（RIG-I）和黑色素瘤分化相关基因5（MDA5）双链RNA传感器相互作用的外来病毒细胞质核酸刺激，但在神经退行性疾病中，天然免疫也会被随着神经元死亡而积累的自身DNA和双链RNA激活。在下游，激活的STING招募TANK结合激酶1（TBK1）并刺激干扰素刺激基因的反式激活和自噬途径，这两者都具有保护作用。然而，天然免疫的慢性激活会导致小胶质细胞激活、神经炎症和自噬失败，进而导致神经退行性变。STING也是一种质子通道，激活时会刺激质子从STING囊泡中流出，导致细胞死亡。在此，我们综述了天然免疫以及胆固醇和脂肪酸合成途径的显著特征、神经退行性疾病中STING和SREBP信号异常的观察结果以及相关治疗方法。
