Multiple Host Factors Interact with the Hypervariable Domain of Chikungunya Virus nsP3 and Determine Viral Replication in Cell-Specific Mode

• DOI: 10.1128/jvi.00838-18
• Publication Date: 2018-06-12T10:00:35Z
• Authors: Chetan D. Meshram; Peter Agback; Nikita Shiliaev; Nadya Urakova; James A. Mobley; Tatiana Agback; Elena I. Frolova; Ilya Frolov
• Keywords: 0301 basic medicine; Binding Sites; Nucleosome Assembly Protein 1; Viral Nonstructural Proteins; Virus Replication; Cell Line; 3. Good health; Mice; 03 medical and health sciences; Culicidae; HEK293 Cells; RNA Recognition Motif Proteins; Protein Domains; Chlorocebus aethiops; NIH 3T3 Cells; Animals; Humans; Chikungunya virus; Vero Cells

Alphaviruses utilize a broad spectrum of cellular factors for efficient formation and function of replication complexes (RCs). Our data demonstrate for the first time that the hypervariable domain (HVD) of chikungunya virus nonstructural protein 3 (nsP3) is intrinsically disordered. It binds at least 3 families of cellular proteins, which play an indispensable role in viral RNA replication. The proteins of each family demonstrate functional redundancy. We provide a detailed map of the binding sites on CHIKV nsP3 HVD and show that mutations in these sites or the replacement of CHIKV HVD by heterologous HVD change cell specificity of viral replication. Such manipulations with alphavirus HVDs open an opportunity for development of new irreversibly attenuated vaccine candidates. To date, the disordered protein fragments have been identified in the nonstructural proteins of many other viruses. They may also interact with a variety of cellular factors that determine critical aspects of virus-host interactions.