Center for Pathogen Biology and Infectious Diseases, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130021, China.
Center for Pathogen Biology and Infectious Diseases, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130021, China.
Virol Sin. 2022 Oct;37(5):676-684. doi: 10.1016/j.virs.2022.07.013. Epub 2022 Aug 5.
Enterovirus 71 (EV71) caused hand, foot and mouth disease (HFMD) is a serious threat to the health of young children. Although type I interferon (IFN-I) has been proven to control EV71 replication, the key downstream IFN-stimulated gene (ISG) remains to be clarified and investigated. Recently, we found that 2'-5'-oligoadenylate synthetases 3 (OAS3), as one of ISG of IFN-β1b, was antagonized by EV71 3C protein. Here, we confirm that OAS3 is the major determinant of IFN-β1b-mediated EV71 inhibition, which depends on the downstream constitutive RNase L activation. 2'-5'-oligoadenylate (2-5A) synthesis activity deficient mutations of OAS3 D816A, D818A, D888A, and K950A lost resistance to EV71 because they could not activate downstream RNase L. Further investigation proved that EV71 infection induced OAS3 but not RNase L expression by IFN pathway. Mechanically, EV71 or IFN-β1b-induced phosphorylation of STAT1, but not STAT3, initiated the transcription of OAS3 by directly binding to the OAS3 promoter. Our works elucidate the immune regulatory mechanism of the host OAS3/RNase L system against EV71 replication.
肠道病毒 71 型（EV71）引起的手足口病（HFMD）是严重威胁婴幼儿健康的疾病。虽然 I 型干扰素（IFN-I）已被证明可以控制 EV71 的复制，但关键的下游干扰素刺激基因（ISG）仍需阐明和研究。最近，我们发现 2'-5'-寡聚腺苷酸合成酶 3（OAS3）作为 IFN-β1b 的 ISG 之一，被 EV71 3C 蛋白拮抗。在这里，我们证实 OAS3 是 IFN-β1b 介导的 EV71 抑制的主要决定因素，这取决于下游组成性核糖核酸酶 L 的激活。OAS3 的 2'-5'-寡聚腺苷酸（2-5A）合成活性缺陷突变 D816A、D818A、D888A 和 K950A 由于不能激活下游的核糖核酸酶 L 而失去对 EV71 的抗性。进一步的研究证明，EV71 感染通过 IFN 途径诱导 OAS3 而不是 RNase L 的表达。在机制上，EV71 或 IFN-β1b 诱导 STAT1 的磷酸化，而不是 STAT3，通过直接结合 OAS3 启动子启动 OAS3 的转录。我们的工作阐明了宿主 OAS3/RNase L 系统对抗 EV71 复制的免疫调节机制。
