Gu Haiyan, Yang Jing, Zhang Jiayu, Song Ying, Zhang Yao, Xu Pengfei, Zhu Yuanxiang, Wang Liangliang, Zhang Pengfei, Li Lin, Chen Dahua, Sun Qinmiao
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Datun Road, Chaoyang District, Beijing, 100101, China.
Institute of Biomedical Research, Yunnan University, Kunming, 650500, China.
Nat Commun. 2022 Mar 23;13(1):1564. doi: 10.1038/s41467-022-29266-9.
Cyclic GMP-AMP synthase (cGAS) plays a major role in detecting pathogenic DNA. It produces cyclic dinucleotide cGAMP, which subsequently binds to the adaptor protein STING and further triggers antiviral innate immune responses. However, the molecular mechanisms regulating cGAS enzyme activity remain largely unknown. Here, we characterize the cGAS-interacting protein Poly(rC)-binding protein 2 (PCBP2), which plays an important role in controlling cGAS enzyme activity, thereby mediating appropriate cGAS-STING signaling transduction. We find that PCBP2 overexpression reduces cGAS-STING antiviral signaling, whereas loss of PCBP2 significantly increases cGAS activity. Mechanistically, we show that PCBP2 negatively regulates anti-DNA viral signaling by specifically interacting with cGAS but not other components. Moreover, PCBP2 decreases cGAS enzyme activity by antagonizing cGAS condensation, thus ensuring the appropriate production of cGAMP and balancing cGAS-STING signal transduction. Collectively, our findings provide insight into how the cGAS-mediated antiviral signaling is regulated.
环鸟苷酸-腺苷酸合成酶（cGAS）在检测病原性DNA中起主要作用。它产生环二核苷酸cGAMP，随后cGAMP与衔接蛋白STING结合，并进一步触发抗病毒固有免疫反应。然而，调节cGAS酶活性的分子机制在很大程度上仍然未知。在此，我们鉴定了与cGAS相互作用的蛋白聚（rC）结合蛋白2（PCBP2），其在控制cGAS酶活性中起重要作用，从而介导适当的cGAS-STING信号转导。我们发现PCBP2的过表达降低了cGAS-STING抗病毒信号，而PCBP2的缺失显著增加了cGAS活性。机制上，我们表明PCBP2通过与cGAS特异性相互作用而非其他成分来负向调节抗DNA病毒信号。此外，PCBP2通过拮抗cGAS凝聚来降低cGAS酶活性，从而确保cGAMP的适当产生并平衡cGAS-STING信号转导。总的来说，我们的研究结果为cGAS介导的抗病毒信号如何被调节提供了见解。
