Abstract
Dengue virus is a pathogen of global concern and has a huge impact on public health system in low- and middle-income countries. The capsid protein of dengue virus is least conserved among related flavivirus and there is very limited information on the role of cytosolic proteins that interact with dengue virus capsid. We identified DEAD (Asp-Glu-Ala-Asp) Box Helicase 3, an X-Linked (DDX3X), cytosolic ATP-dependent RNA helicase as a dengue virus capsid-interacting protein. We show that the N-terminal region of capsid is important for interaction with DDX3X, while the N-terminal domain of DDX3X seems to be involved in interaction with dengue capsid. DDX3X was down-regulated in dengue virus infected cells at later stages of infection. Our results show that DDX3X is an antiviral protein as suppression of DDX3X expression by siRNA led to an increase in viral titers and overexpression of DDX3X led to inhibition of viral replication. Knock-down of DDX3X did not affect induction of type I interferon response upon infection suggesting that the effect of DDX3X knock-down is independent of the interferon-dependent pathways that DDX3X modulates under normal conditions. Thus, our study identifies DDX3X as a dengue virus capsid interacting protein and indicates a potential link between the antiviral functions of DDX3X and dengue capsid at later stages of dengue infection.
Highlights
Dengue is the most common mosquito-borne viral disease in tropical and subtropical areas, with an estimated 50–100 million infections occurring each year
We have identified DDX3X as a Dengue virus (DENV) capsid-interacting protein and further confirm its anti-viral role in DENV infection
We show that the N-terminal 45 amino acids including the αhelix-1 of DENV-C was essential for interaction with DDX3X
Summary
Dengue is the most common mosquito-borne viral disease in tropical and subtropical areas, with an estimated 50–100 million infections occurring each year. Sequential cleavages of the anchored capsid protein by viral protease and host signalase result in removal of the C-terminal trans-membrane region to yield the 100-residue mature form, Dengue Capsid Interacts with DDX3X which is a highly basic 12 kDa protein (Amberg et al, 1994; Yamshchikov and Compans, 1995; Sangiambut et al, 2008, 2013). A number of host proteins have been identified as capsid-interacting proteins for various flaviviruses and these studies implicate capsid in a variety of functions such as lipid metabolism, apoptosis and stress granule formation (Byk and Gamarnik, 2016). Recent studies have proposed a role for JEV capsid protein in blocking stress granule formation and relieving translation repression by interaction with Caprin-1 (Katoh et al, 2013). DENV capsid was shown to colocalize with MX1/MxA, an interferon-induced GTPase involved in antiviral signaling in primary endothelial cells infected with DENV-2 suggesting a role for capsid protien in blocking antiviral pathways (Kanlaya et al, 2010)
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