Neuralized E3 Ubiquitin Protein Ligase 3 Is an Inducible Antiviral Effector That Inhibits Hepatitis C Virus Assembly by Targeting Viral E1 Glycoprotein

Abstract

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV can be sensed by host innate immunity to induce expression of interferons (IFNs) and a number of antiviral effectors. In this study, we found HCV infection induced the expression of Neuralized E3 Ubiquitin Protein Ligase 3 (NEURL3), a putative E3 ligase, in a manner that requires the involvement of innate immune sensing but is independent of the IFN action. Furthermore, we showed that NEURL3 inhibited HCV infection, while had little effect on other RNA viruses including zika virus, dengue virus and vesicular stomatitis virus. Mechanistic studies demonstrated that NEURL3 inhibited HCV assembly by directly binding HCV envelope glycoprotein E1 to interfere with the E1/E2 heterodimerization, an important prerequisite for virion morphogenesis. Finally, we showed that knockout of NEURL3 significantly enhanced HCV infection. In summary, we identified NEURL3 as a novel inducible antiviral host factor that suppresses HCV assembly. Our results not only shed new insight into how host innate immunity acts against HCV, but also revealed a new important biological function for NEURL3. The exact biological function of NEURL3, a putative E3 ligase remains largely unknown. In this study, we found that NEURL3 could be upregulated upon HCV infection in a manner dependent on pattern-recognition receptor-mediated innate immune response. NEURL3 inhibits HCV assembly by directly binding viral E1 envelope glycoprotein to disrupt its interaction with E2, an action that requires its NHR domain but not RING domain. Furthermore, we found that NEURL3 has a pan-genotypic anti-HCV activity and interacts with E1 of genotype 2a, 1b, 3a and 6a, but does not inhibit other closely related RNA viruses such as ZIKV, DENV and VSV. To our knowledge, our study is the first report to demonstrate that NEURL3 functions as an antiviral host factor. Our results not only shed new insight into how host innate immunity acts against HCV, but also revealed a new important biological function for NEURL3.

Embryonic endothelial evolution towards first hematopoietic stem cells revealed by single-cell transcriptomic and functional analyses

“…4h), supportive of the cluster assignment. Belonging to the gene family of E3 ubiquitin ligases, the expression and role of Neurl3 in spermatogenesis and inflammation have been reported, [43][44][45] whereas that relevant to vascular and hematopoietic development remain barely known. Neurl3 was screened out by unsupervised bioinformatics analysis, and fortunately, its expression in the AGM region was restricted to aorta and largely consistent with that of Runx1 both transcriptomically (Supplementary information, Fig.…”

A New Likelihood-based Test for Natural Selection

“…The NEURL3 gene encodes the neuralized E3 ubiquitin protein ligase 3 (NEURL3), which inhibits hepatitis C virus (HCV) infection. Knockout of this gene has been shown to promote HCV infectivity (Zhao et al, 2018). Similarly to the case with the TMEM127 gene, it is plausible that the signal of non-neutrality detected at this locus is also caused by negative selection operating against deleterious mutations to this gene.…”

Direct Interaction Between CD163 N-Terminal Domain and MYH9 C-Terminal Domain Contributes to Porcine Reproductive and Respiratory Syndrome Virus Internalization by Permissive Cells

“…The assay was performed as previously described (Zhao et al, 2018). PAMs were seeded onto glass coverslips, each with a diameter of 14 mm, and cells on coverslips were incubated with SRCR1-4-His for 2 h at 37°C.…”