Nucleolin Interacts with the Dengue Virus Capsid Protein and Plays a Role in Formation of Infectious Virus Particles

Abstract

Dengue virus (DENV), a member of the genus Flavivirus, causes a spectrum of disease in humans that can range from a mild febrile illness to potentially fatal hemorrhage or shock syndromes. Four serotypes of DENV (DENV-1, -2, -3, and -4) are transmitted by the bite of a mosquito vector and are responsible for more than 50 million infections each year. Infection with one DENV serotype does not confer lasting immunity to the others (1-3). The most severe clinical manifestations of dengue are associated with secondary infections by a heterologous DENV serotype (2). Increasing urbanization, cocirculation of multiple DENV serotypes within the same geographic area, and expansion of its insect vector contribute to the increasing importance of dengue to global health (2, 3).DENV contains a positive-sense single-stranded RNA (ssRNA) genome that is translated as a single open reading frame. The resulting polyprotein is cleaved by virus and host proteases into three structural and at least seven nonstructural proteins (4, 5). The capsid (C) protein functions as a structural component of the DENV virion, encapsulating the ssRNA genome of the virus (4, 5). The DENV C protein is composed of four alpha helices with an unstructured amino terminus and forms antiparallel homodimers.

Development and characterization of polyclonal peptide antibodies for the detection of Yellow fever virus proteins

“…In addition to the characteristic fluorescence signal in the cytoplasm of YFV infected cells, a strong fluorescence was observed in the nuclear region as one or several distinct spots, indicating accumulation of the C protein in the nucleus. To our knowledge, this is the first reference of YFV-C protein nuclear localization, while it has been reported already for other flaviviruses (Wang et al, 2002;Mori et al, 2005;Balinsky et al, 2013;Bulich and Aaskov, 1992;Westaway et al, 1997;Bhuvanakantham et al, 2009;Colpitts et al, 2011). Further work is required to support this finding for YFV and to investigate the interaction of the C protein with host proteins as well as its role in viral pathogenesis.…”

“…In addition, a location of the C protein in the nucleus of infected cells and interaction with different cellular proteins has been documented for several flaviviruses, implying a relevant role in viral replication and the virus-host interplay (Wang et al, 2002;Mori et al, 2005;Balinsky et al, 2013;Bulich and Aaskov, 1992;Westaway et al, 1997;Bhuvanakantham et al, 2009;Colpitts et al, 2011). Analogous localization and interaction has not yet been proven for YFV.…”

Characterization of the Mode of Action of a Potent Dengue Virus Capsid Inhibitor

“…For Japanese encephalitis virus, it was shown that disrupting nuclear localization affected virus replication and pathogenesis in mice (37). In the case of DV, several studies reported the presence of C protein in the nucleoli of infected cells (28,33,34,38). Moreover, DV C protein has been shown to interact with a number of nuclear proteins, including hnRNP-K and histones (39,40,41); however, the relevance of nuclear localization of DV C protein with respect to viral replication is unclear (28).…”

“…In DV-infected cells, C protein resides both in the cytoplasm and nucleus (28,29,30). Cytosolic capsid protein was shown to localize around LDs (15) and in close association with vesicle packets, which are sites of RNA replication (30,31,32), while nuclear capsid protein accumulates in nucleoli and was reported to interact with nuclear proteins (33,34,35). In order to investigate whether ST-148 would affect the recruitment of capsid to LDs and its colocalization with dsRNA, we performed colocalization studies using DV-infected cells treated with ST-148.…”

Capsid, membrane and NS3 are the major viral proteins involved in autophagy induced by Japanese encephalitis virus

“…In JEV, nuclear localization of the capsid protein and its binding with the host nucleolar protein B23 are recognized to be important for the replication of JEV (Tsuda et al, 2006). In other flaviviruses, the core protein of hepatitis C virus (HCV) is shown to evoke autophagy by EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression , and dengue virus C protein with a NCL binding aptamer AS1411 is supposed to play a role in formation of infectious virus particles (Balinsky et al, 2013). Recent findings have shown that the membrane protein of flavivirus is essential for the formation of immature virion and takes part in the process of viral particle assembly in the infected cells (Yoshii et al, 2011).…”