College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, Henan Province, PR China.
College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, Henan Province, PR China.
Mol Immunol. 2018 Mar;95:56-63. doi: 10.1016/j.molimm.2018.01.008. Epub 2018 Feb 20.
In a previous study, we demonstrated that porcine cyclic GMP-AMP (cGAMP) synthase (cGAS) catalyzes cGAMP production and is an important DNA sensor for the pseudorabies virus (PRV)-induced activation of interferon β (IFN-β). Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) has recently been identified as the hydrolase of cGAMP in rodents, but its role in porcine cells is not clear. Our recent study demonstrated that porcine ENPP1 is responsible for the homeostasis of cGAMP and is critical for PRV infection. Porcine ENPP1 mRNA is predominantly expressed in muscle. PRV infection was enhanced by ENPP1 overexpression and attenuated by silencing of ENPP1. During PRV infection, the activation of IFN-β and NF-κB was reduced in ENPP1 overexpressed cells and promoted in ENPP1 knockdown cells. Investigation of the molecular mechanisms of ENPP1 during PRV infection showed that ENPP1 hydrolyzed cGAMP in PRV-infected or cGAMP-transfected cells and inhibited IRF3 phosphorylation, reducing IFN-β secretion. These results, combined with those for porcine cGAS, demonstrate that ENPP1 acts coordinately with cGAS to maintain the reservoir of cGAMP and participates in PRV infection.
在之前的一项研究中，我们证明猪环状鸟苷酸-腺苷酸（cGAMP）合酶（cGAS）催化 cGAMP 的产生，是伪狂犬病病毒（PRV）诱导干扰素β（IFN-β）激活的重要 DNA 传感器。最近发现核苷酸焦磷酸酶磷酸二酯酶 1（ENPP1）是啮齿动物中 cGAMP 的水解酶，但它在猪细胞中的作用尚不清楚。我们最近的研究表明，猪 ENPP1 负责 cGAMP 的动态平衡，对 PRV 感染至关重要。猪 ENPP1 mRNA 主要在肌肉中表达。ENPP1 的过表达增强了 PRV 的感染，而 ENPP1 的沉默则减弱了 PRV 的感染。在 PRV 感染过程中，IFN-β和 NF-κB 的激活在 ENPP1 过表达的细胞中被减弱，而在 ENPP1 敲低的细胞中被增强。对 PRV 感染过程中 ENPP1 的分子机制的研究表明，ENPP1 在 PRV 感染或 cGAMP 转染的细胞中水解 cGAMP，抑制 IRF3 磷酸化，减少 IFN-β 的分泌。这些结果与猪 cGAS 的结果相结合，表明 ENPP1 与 cGAS 协同作用，维持 cGAMP 的储备，并参与 PRV 感染。
