EFTUD2 Is a Novel Innate Immune Regulator Restricting Hepatitis C Virus Infection through the RIG-I/MDA5 Pathway

Abstract

The elongation factor Tu GTP binding domain-containing protein 2 (EFTUD2) was identified as an anti-hepatitis C virus (HCV) host factor in our recent genome-wide small interfering RNA (siRNA) screen. In this study, we sought to further determine EFTUD2's role in HCV infection and investigate the interaction between EFTUD2 and other regulators involved in HCV innate immune (RIG-I, MDA5, TBK1, and IRF3) and JAK-STAT1 pathways. We found that HCV infection decreased the expression of EFTUD2 and the viral RNA sensors RIG-I and MDA5 in HCV-infected Huh7 and Huh7.5.1 cells and in liver tissue from in HCVinfected patients, suggesting that HCV infection downregulated EFTUD2 expression to circumvent the innate immune response. H epatitis C virus (HCV) poses a threat to public health by infecting approximately 170 million people worldwide and causing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (1, 2). Fifty to ninety percent of acute infections become chronic due to failure to mount a productive immune response to clear the virus. The innate immune system is the first line of defense responsible for recognizing viral pathogens and is therefore one of the crucial elements in determining the outcome of HCV infection.It is known that HCV RNA is recognized by the combined actions of protein kinase R (PKR), retinoic acid-inducible gene 1 (RIG-I), and Toll-like receptor 3 (TLR3) after viral entry into host cells (3-5). Pathogen recognition triggers downstream signaling to activate transcription factors, such as interferon (IFN) regulatory factors (IRFs), to induce type I interferon secretion and stimulation of the JAK-STAT signaling pathway, leading to the expression of IFN-stimulated genes (ISGs), which presumptively mediate control of viral replica-

A Long Noncoding RNA Regulates Hepatitis C Virus Infection Through Interferon Alpha–Inducible Protein 6

“…Because the Huh7.5.1 cell line is an immortalized cell line with deficiencies in the RIG-I pathway, (21) we therefore validated our findings in PHHs. We confirmed that lncRNA-IFI6 gRNA inhibited lncRNA-IFI6 expression, and IFNα induced lncRNA-IFI6 expression in uninfected and JFH1-infected PHHs (Supporting Fig.…”

“…lncRNAs have been reported to play important roles in regulation of the IFN response and ISGs in HCV infection . We previously have demonstrated that HCV infection regulated ISGs through the Jak‐Stat pathway . We therefore speculate that HCV’s effects on lncRNA IFI6 and IFI6 expression are mediated through innate immune signaling pathways.…”

“…(27) We previously have demonstrated that HCV infection regulated ISGs through the Jak-Stat pathway. (20,21,49,50) We therefore speculate that HCV's effects on lncRNA IFI6 and IFI6 expression are mediated through innate immune signaling pathways. These results further add to our understanding of the regulatory mechanisms of noncoding RNAs in the context of chronic HCV and the exhausted ISG phenotype, and will assist the development of applications that may prevent the establishment of persistent HCV infection, as well as potentially other viral infections.…”

NV Proteins of Fish Novirhabdovirus Recruit Cellular PPM1Bb Protein Phosphatase and Antagonize RIG-I-Mediated IFN Induction

“…On the other hand, EFTUD2 is a GTPase which is a component of the spliceosome complex which processes precursor mRNAs to produce mature mRNAs. In a recent study, the level of expression of RIG-I and MDA5 has been shown to be linked to that of EFTUD2, suggesting that EFTUD2 controls the expression of these viral sensors38. Moreover, silencing EFTUD2 only reduces mature mRNA of both sensors and has no effect on pre-mRNA amounts, suggesting that EFTUD2 regulates RIG-I and MDA5 through mRNA splicing.…”

Rotavirus Infection Alters Splicing of the Stress-Related Transcription Factor XBP1

“…Exon skipping in XBP1 could be another means of inducing the synthesis of a functional XBP1 transcription factor in the course of a cellular response to infection. Relevant to this hypothesis, alternative splicing has been shown to regulate host antiviral responses (73,74), and pathways linking splicing regulation with the antiviral response are now considered emerging mechanisms of evasion in viral infection (72,(74)(75)(76)(77).…”