Liu Heng, Zhang Lele, Sun Jin, Chen Wei, Li Senlin, Wang Qiang, Yu Huansha, Xia Zanxian, Jin Xia, Wang Chen
State Key Laboratory of Molecular Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Viral Disease and Vaccine Translational Research Unit, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
J Virol. 2017 Apr 13;91(9). doi: 10.1128/JVI.02234-16. Print 2017 May 1.
Dengue viruses (DENVs) are an emerging threat to global public health. The NS2B3 protease complex of DENV has recently been shown to cleave the antiviral protein STING and thereby subvert the innate immune signaling to facilitate virus replication. Whether host cells have a mechanism to counteract this virus-mediated immunosuppression is unclear. We discovered that the K27-linked polyubiquitination of NS3 protein facilitates its recruitment of NS2B, the formation of NS2B3, and consequently the enhanced cleavage of STING. However, an endoplasmic reticulum (ER) protein, SCAP, through binding to NS2B protein, inhibits the ubiquitination of NS3, rendering NS2B3 protease incapable of binding and cleaving STING. Importantly, ectopic expression of SCAP impaired DENV infection, whereas silencing of SCAP potentiated DENV infection. Collectively, this study uncovered a novel function of SCAP of counteracting the inhibitory action of DENV NS2B3 protease on STING signaling, suggesting that modulation of SCAP levels may have therapeutic implications. This study reports the first ubiquitylation target protein in DENV, the NS3 protein, and the unique role of K27-linked polyubiquitylation in NS3's ability to recruit NS2B and formation of the NS2B3 protease complex. Additionally, this study identified novel functions of the ER protein SCAP: one is to compete with NS2B for binding to STING, and the other is to inhibit the ubiquitination of NS3. Both of these functions protect STING from being cleaved by the NS2B3 protease and thus contribute to host antiviral response.
登革病毒（DENVs）是对全球公共卫生的一种新出现的威胁。最近研究表明，登革病毒的NS2B3蛋白酶复合物可切割抗病毒蛋白STING，从而破坏先天免疫信号传导以促进病毒复制。宿主细胞是否有机制来对抗这种病毒介导的免疫抑制尚不清楚。我们发现，NS3蛋白的K27连接的多聚泛素化促进了其对NS2B的招募、NS2B3的形成，进而增强了对STING的切割。然而，一种内质网（ER）蛋白SCAP通过与NS2B蛋白结合，抑制了NS3的泛素化，使NS2B3蛋白酶无法结合和切割STING。重要的是，SCAP的异位表达损害了登革病毒感染，而SCAP的沉默则增强了登革病毒感染。总的来说，这项研究揭示了SCAP的一种新功能，即对抗登革病毒NS2B3蛋白酶对STING信号传导的抑制作用，这表明调节SCAP水平可能具有治疗意义。本研究报道了登革病毒中第一个泛素化靶蛋白NS3蛋白，以及K27连接的多聚泛素化在NS3招募NS2B和形成NS2B3蛋白酶复合物能力中的独特作用。此外，本研究还确定了内质网蛋白SCAP的新功能：一是与NS2B竞争结合STING，二是抑制NS3的泛素化。这两种功能都保护STING不被NS2B3蛋白酶切割，从而有助于宿主的抗病毒反应。
