Date Published: August 24, 2018
Publisher: Public Library of Science
Author(s): Kezhen Wang, Chunling Zou, Xiujuan Wang, Chenxiao Huang, Tingting Feng, Wen Pan, Qihan Wu, Penghua Wang, Jianfeng Dai, Sonja Best.
In order to eliminate viral infections, hundreds of interferon-stimulated genes (ISGs) are induced via type I interferons (IFNs). However, the functions and mechanisms of most ISGs are largely unclear. A tripartite motif (TRIM) protein encoding gene TRIM69 is induced by dengue virus (DENV) infection as an ISG. TRIM69 restricts DENV replication, and its RING domain, which has the E3 ubiquitin ligase activity, is critical for its antiviral activity. An in vivo study further confirmed that TRIM69 contributes to the control of DENV infection in immunocompetent mice. Unlike many other TRIM family members, TRIM69 is not involved in modulation of IFN signaling. Instead, TRIM69 interacts with DENV Nonstructural Protein 3 (NS3) directly and mediates its polyubiquitination and degradation. Finally, Lys104 of NS3 is identified as the target of TRIM69-mediated ubiquitination. Our study demonstrates that TRIM69 restricts DENV replication by specifically ubiquitinating a viral nonstructural protein.
Recently, mosquito-borne viral diseases become global threats to human health. As the most significant mosquito-borne viral pathogen, Dengue virus (DENV) is responsible for outbreaks of dengue fever (DF), dengue shock syndrome (DSS), and dengue hemorrhagic fever (DHF). DENV causes millions of infections in over 100 countries annually, resulting in more than 25,000 deaths [1,2]. A DENV vaccine was recently licensed for use after several decades of efforts, however, it confers only partial cross protection for all DENV serotypes [3,4]. Additionally, there is still no antiviral drugs have been approved to treat DENV induced diseases [5,6].
This work has illustrated a TRIM family member, TRIM69, as a key host factor needed to restrict DENV infection. TRIM69 mRNA was found to be overexpressed in 293T cells infected with DENV-2 as determined by RNA-Seq analysis. A significant amount of differential expressed genes found in virus infected cells have been described as signaling pathway molecules involved in antiviral innate immunity (S1 Fig). 52 out of the 99 upregulated genes are predicted ISGs, such as TRIM69, LGALS3BP, C19ORF66, DDX60, and HELZ2 (S2 Fig). All of these putative ISGs were upregulated after DENV infection (S2 Fig). Consistent with our results, two recent studies also report that both C19ORF66 and HELZ2 are induced by IFN and suppress DENV replication [55,56]. A previous report identified that TRIM69 is induced in peripheral blood cells upon type I IFN stimulation , here we show that TRIM69 is also upregulated in 293T, HUVEC, and HFF cells by IFN-β stimulation or virus infection (Fig 1), and has antiviral properties against DENV infection.