Nucleolin Regulates the Expression of Kaposi’s Sarcoma-Associated Herpesvirus’ Latency-Associated Nuclear Antigen through G-Quadruplexes in the mRNA

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes life-long latent infection and is linked to several human malignancies. Latency-associated nuclear antigen (LANA) is highly expressed during latency, and is responsible for the replication and maintenance of the viral genome. The expression of LANA is regulated at transcriptional/translational levels through multiple mechanisms, including the secondary structures in the mRNA sequence. LANA mRNA has multiple G-quadruplexes (G4s) that are bound by multiple proteins to stabilize/destabilize these secondary structures for regulating LANA. In this manuscript, we demonstrate the role of Nucleolin (NCL) in regulating LANA expression through its interaction with G-quadruplexes of LANA mRNA. This interaction reduced LANA’s protein expression through the sequestration of mRNA into the nucleus, demonstrated by the colocalization of G4-carrying mRNA with NCL. Furthermore, the downregulation of NCL, by way of a short hairpin, showed an increase in LANA translation following an alteration in the levels of LANA mRNA in the cytoplasm. Overall, the data presented in this manuscript showed that G-quadruplexes-mediated translational control could be regulated by NCL, which can be exploited for controlling KSHV latency.

G-Quadruplexes in the Regulation of Viral Gene Expressions and Their Impacts on Controlling Infection

“…hnRNP A1 functions as a helicase, destabilizing the G4 secondary structure, leading to increased LANA translation and enhanced antigen presentation [175]. Contrastingly, NCL stabilizes the same G4 hnRNPA1 unwinds, resulting in reduced LANA translation and reduced antigen presentation [182]. Therefore, if this interaction can be destabilized, antigen presentation is increased, allowing the host immune system to detect and eliminate infected cells.…”