cGAS-STING信号通路和疾病

在宿主抵抗病毒感染和细菌入侵的过程中,cGAS-STING通路发挥着重要作用.在这一过程中胞质游离DNA作为危险信号被DNA感受器环GMP-AMP合酶(cGAS)所识别.cGAS可识别双链DNA,催化三磷酸腺苷(ATP)和三磷酸鸟苷(GTP)合成非经典环二核苷酸2'5'-cGAMP.其下游的干扰素刺激基因(STING)作为衔接分子,既可直接识别细菌产生的第二信使——环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP),也可作为信号受体,识别cGAS感受胞质DNA产生的cGAMP;随后激活下游信号,促进Ⅰ型干扰素和其他细胞因子的产生,从而产生相应的免疫应答.不仅外源细菌或病毒DNA,自身胞质DNA的异常沉积也会激活该通路,从而导致自身炎症和自身免疫疾病.后续研究发现,这一通路在肿瘤放射治疗和化学治疗中同样发挥重要作用,通过激活cGAS-STING通路产生或增强对肿瘤的治疗.研究结果表明,特异性干扰cGAS-STING通路的激活可能对肿瘤、感染、免疫疾病的治疗提供依据.对cGAS-STING通路激活机制及其与疾病治疗的关系作了全面概述,并对cGAS-STING通路的调节作了详细介绍.

cGAS-STING signaling pathway and diseases

The cGAS-STING pathway plays a significant role in host defense against viral and bacterial infection.In the process,the cytoplasmic free DNA,considered as a danger signal,is recognized by nucleotidyl transferase cGAS.cGAS is activated by double-stranded DNA (dsDNA) and catalyzes the synthesis of a noncanonical cyclic dinucleotide 2'5'-cGAMP from adenosine triphosphate (ATP) and guanosine triphosphate (GTP).cGAMP serve as an endogenous second messenger to stimulate the induction of type Ⅰ interferons via STING.In addition to the exogenous bacterial or viral DNA,abnormal deposition of host DNA in cytosol also activates the cGAS-STING signaling pathway cascade,resulting in inflammation and autoimmune diseases.Subsequent studies found that this pathway also plays an important role in tumor's responsiveness to radio-therapy and chemo-therapy.Activation of cGAS-STING pathway produces or enhances the therapeutic efficacy.These findings suggest that specifically interfering with cGAS-STING activation may hold therapeutic value for the treatment of cancer,infection and inflammatory diseases.In this paper,the activation mechanism of cGAS-STING pathway and its relationship with the treatment of diseases were summarized,and the regulation of cGAS-STING pathway was introduced in detail.