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An Integrated System Approach Identified the Human Proteasome as a Conserved Critical Machinery for ZIKV and DENV Replication

Zika virus (ZIKV) and dengue virus (DENV) are two related flaviviruses that share similar replication process but exhibit distinct clinical outcomes. Systematic understanding of virus‐host cell interaction networks can reveal cellular pathways not only critical for viral replication but also for pathogenesis. Here we employed a protein array approach to comprehensively identify host proteins interacted by both ZIKV and DENV proteins. The results uncovered multiple conserved host pathways and cellular protein complexes that are engaged by both viruses, such as proteasome complex and spliceosomal complex, involving in flavivirus infections. An RNAi screening of 10,415 druggable genes found that the proteins such as these related to proteasome significantly reduced ZIKV infection. Additionally, a high‐throughput screening of bioactive compound collections identified 134 compounds with anti‐ZIKV activity. Among these compounds, eight proteasome inhibitors suppressed both ZIKV and DENV replication. This system biology approach integrating the orthogonal pathways and protein‐protein interactions has revealed the proteasome as a critical host machinery for ZIKV replication. This study provides rich and valuable datasets for further studies of flavivirus‐host interactions, disease pathogenesis, and new drug targets.