Host mRNA 3′-end processing machinery are critical binding partners during dengue virus infection

Dengue virus (DENV) causes a wide variety of dengue diseases that threaten over half of the world′s population. At present, there is no antiviral therapeutics against dengue. Virus infection and its associated pathologies are the result of a myriad of interactions between the virus and its host, of which most are protein-protein interactions (PPIs). Virus-encoded proteins modulate the host environment for the virus′ benefit by interacting with host proteins during infection. Thus studies of these virus-host PPIs are most informative when performed in the context of an infection. We undertook a comparative affinity purification-mass spectrometry approach to generate a DENV-host protein-protein interactome during DENV infection and identified mRNA 3′-end processing protein complexes as novel interactors of DENV NS3. We demonstrated that the presence of the cleavage and polyadenylation specificity factor complex proteins, but not their enzymatic activity, is crucial for DENV replication, thus unveiling a potential new direction for the development of host-directed antiviral therapeutics.