The Dengue Virus NS5 Protein Intrudes in the Cellular Spliceosome and Modulates Splicing.

DE MAIO F.; IGLESIAS NG.; GEBHARD LG,; MAMMI P.; MANCINI E, ; YANOVSKY MJ, .; ANDINO R, ; KROGAN N,; SREBROW A, ; GAMARNIK AV

PLOS PATHOGENS

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2016 vol. 12

1553-7366

Dengue virus NS5protein plays multiple functions in the cytoplasm of infected cells, enablingviral RNA replication and counteracting host antiviral responses.  Here, we demonstrate a novel function of NS5in the nucleus where it interferes with cellular splicing. Using global proteomicanalysis of infected cells together with functional studies, we found that NS5integrates active spliceosome complexes and modulates endogenous splicing. Inparticular, we show that NS5 alone or in the context of viral infection bindscore components of the U5 snRNP particle, CD2BP2 and DDX23, alters the inclusion/exclusionratio of alternative splicing events, andchanges mRNA isoform abundance of known antiviral factors. Differentmechanistic studies indicate that binding of NS5 to the spliceosome reduces theefficiency of pre-mRNA processing, independently of NS5 enzymatic activities. We propose that NS5 binding to U5 snRNP protein components hijacks the splicing machinery resultingin a less restrictive environment for viral replication.