PCBP2 maintains antiviral signaling homeostasis by regulating cGAS enzymatic activity via antagonizing its condensation

Haiyan Gu, Jing Yang, Jiayu Zhang, Ying Song, Yao Zhang, Pengfei Xu, Yuanxiang Zhu, Liangliang Wang, Pengfei Zhang, Lin Li, Dahua Chen () and Qinmiao Sun ()
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Haiyan Gu: Institute of Zoology, Chinese Academy of Sciences
Jing Yang: Institute of Zoology, Chinese Academy of Sciences
Jiayu Zhang: Institute of Zoology, Chinese Academy of Sciences
Ying Song: Yunnan University
Yao Zhang: Yunnan University
Pengfei Xu: Yunnan University
Yuanxiang Zhu: Yunnan University
Liangliang Wang: Yunnan University
Pengfei Zhang: Institute of Zoology, Chinese Academy of Sciences
Lin Li: Institute of Zoology, Chinese Academy of Sciences
Dahua Chen: Yunnan University
Qinmiao Sun: Institute of Zoology, Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29266-9

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