An Integrated Systems Biology Approach Identifies the Proteasome as A Critical Host Machinery for ZIKV and DENV Replication.
An Integrated Systems Biology Approach Identifies the Proteasome as A Critical Host Machinery for ZIKV and DENV Replication.
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综合系统生物学方法确定蛋白酶体是ZIKV和DENV复制的关键宿主机制。
DOI：
10.1016/j.gpb.2020.06.016
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Zhu H
中科院分区：
文献类型：
--
作者：
Song G;Lee EM;Pan J;Xu M;Rho HS;Cheng Y;Whitt N;Yang S;Kouznetsova J;Klumpp-Thomas C;Michael SG;Moore C;Yoon KJ;Christian KM;Simeonov A;Huang W;Xia M;Huang R;Lal-Nag M;Tang H;Zheng W;Qian J;Song H;Ming GL;Zhu H
寨卡病毒（ZIKV）和登革病毒（DENV）黄病毒表现出相似的复制过程，但具有不同的临床结果。对病毒-宿主蛋白质-蛋白质相互作用网络的系统理解可以揭示病毒复制和疾病发病机制的关键细胞途径。在这里，我们采用了三种独立的系统生物学方法来实现这一目标。首先，单个ZIKV/DENV病毒蛋白与20，240种人类蛋白之间的直接相互作用的蛋白质阵列分析揭示了多种保守的细胞途径和蛋白质复合物，包括蛋白酶体复合物。第二，对10,415个可药用基因的RNAi筛选鉴定了ZIKV感染所需的宿主蛋白，并发现蛋白酶体蛋白在这一过程中至关重要。第三，对6016种生物活性化合物进行高通量筛选以抑制ZIKV，得到134种有效化合物，包括6种抑制ZIKV和DENV复制的蛋白酶体抑制剂。这些正交数据集的综合分析将蛋白酶体确定为ZIKV/DENV复制的关键宿主机制。我们的研究为进一步研究黄病毒-宿主相互作用、疾病发病机制和新的药物靶点提供了多组学数据集。
The Zika virus (ZIKV) and dengue virus (DENV) flaviviruses exhibit similar replicative processes but have distinct clinical outcomes. A systematic understanding of virus–host protein–protein interaction networks can reveal cellular pathways critical to viral replication and disease pathogenesis. Here we employed three independent systems biology approaches toward this goal. First, protein array analysis of direct interactions between individual ZIKV/DENV viral proteins and 20,240 human proteins revealed multiple conserved cellular pathways and protein complexes, including proteasome complexes. Second, an RNAi screen of 10,415 druggable genes identified the host proteins required for ZIKV infection and uncovered that proteasome proteins were crucial in this process. Third, high-throughput screening of 6016 bioactive compounds for ZIKV inhibition yielded 134 effective compounds, including six proteasome inhibitors that suppress both ZIKV and DENV replication. Integrative analyses of these orthogonal datasets pinpoint proteasomes as critical host machinery for ZIKV/DENV replication. Our study provides multi-omics datasets for further studies of flavivirus–host interactions, disease pathogenesis, and new drug targets.
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