Splicing factor SF3B3,a NS5-binding protein,restricts ZIKV infection by targeting GCH1  

作　　者：Tanxiu Chen Hao Yang Penghui Liu Moliduer Hamiti Xintian Zhang Yi Xu Wenqi Quan Yong Zhang Wenhai Yu Li Jiao Tingfu Du Juemin Xi Bin Yin Wei Zhou Shuaiyao Lu Xiaozhong Peng 

机构地区：[1]Institute of Medical Biology,Chinese Academy of Medical Sciences and Peking Union Medical College,Kunming,650031,China [2]Department of Science and Education,Jiangxi Key Laboratory of Translational Cancer Research,Jiangxi Cancer Hospital,Nanchang,330029,China [3]The State Key Laboratory of Medical Molecular Biology,Department of Molecular Biology and Biochemistry,Institute of Basic Medical Sciences,Medical Primate Research Center,Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,100730,China

出　　处：《Virologica Sinica》2023年第2期222-232,共11页中国病毒学（英文版）

基　　金：supported by the National Key R&D Project of China(2021YFC230170402);CAMS Innovation Fund for Medical Sciences(2021-1-I2M-038).

摘　　要：Zika virus(ZIKV),a positive-sense single-stranded RNA virus,causes congenital ZIKV syndrome in children and Guillain-Barre Syndrome(GBS)in adults.ZIKV expresses nonstructural protein 5(NS5),a large protein that is essential for viral replication.ZIKV NS5 confers the ability to evade interferon(IFN)signalling;however,the exact mechanism remains unclear.In this study,we employed affinity pull-down and liquid chromatography-tandem mass spectrometry(LC-MS/MS)analyses and found that splicing factor 3b subunit 3(SF3B3)is associated with the NS5-Flag pull-down complex through interaction with NS5.Functional assays showed that SF3B3 overexpression inhibited ZIKV replication by promoting IFN-stimulated gene(ISG)expression whereas silencing of SF3B3 inhibited expression of ISGs to promote ZIKV replication.GTP cyclohydrolase I(GCH1)is the first and ratelimiting enzyme in tetrahydrobiopterin(BH4)biosynthesis.NS5 upregulates the expression of GCH1 during ZIKV infection.And GCH1 marginally promoted ZIKV replication via the IFN pathway.Additionally,GCH1 expression is related to the regulation of SF3B3.Overexpression of the SF3B3 protein effectively reduced GCH1 protein levels,whereas SF3B3 knockdown increased its levels.These findings indicated that ZIKV NS5 binding protein SF3B3 contributed to the host immune response against ZIKV replication by modulating the expression of GCH1.

关 键 词：Nonstructural protein 5(NS5) Splicing factor 3b subunit 3(SF3B3) GTP cyclohydrolase I(GCH1) IFN-stimulated gene(ISGs) IFN signalling Pathway 

分 类 号：R373.3[医药卫生—病原生物学]