RIG-I is a cytosolic pathogen recognition receptor that engages viral RNA in infected cells to trigger innate immune defenses through its adaptor protein MAVS. MAVS resides on mitochondria and peroxisomes, but how its signaling is coordinated among these organelles has not been defined. Here we show that a major site of MAVS signaling is the mitochondrial-associated membrane (MAM), a distinct membrane compartment that links the endoplasmic reticulum to mitochondria. During RNA virus infection, RIG-I is recruited to the MAM to bind MAVS. Dynamic MAM tethering to mitochondria and peroxisomes then coordinates MAVS localization to form a signaling synapse between membranes. Importantly, the hepatitis C virus NS3/4A protease, which cleaves MAVS to support persistent infection, targets this synapse for MAVS proteolysis from the MAM, but not from mitochondria, to ablate RIG-I signaling of immune defenses. Thus, the MAM mediates an intracellular immune synapse that directs antiviral innate immunity.interferon | IPS-1

Summary RIG-I is a cytosolic pathogen recognition receptor that initiates immune responses against RNA viruses. Upon viral RNA recognition, anti-viral signalling requires RIG-I redistribution from the cytosol to membranes where it binds the adaptor protein, MAVS. Here we identify the mitochondrial targeting chaperone protein, 14-3-3ε, as a RIG-I-binding partner and essential component of a translocation complex or “translocon” containing RIG-I, 14-3-3ε, and the TRIM25 ubiquitin ligase. The RIG-I translocon directs RIG-I redistribution from the cytosol to membranes where it mediates MAVS-dependent innate immune signalling during acute RNA virus infection. 14-3-3ε is essential for the stable interaction of RIG-I with TRIM25, which facilitates RIG-I ubiquitination and initiation of innate immunity against hepatitis C virus and other pathogenic RNA viruses. Our results define 14-3-3ε as a key component of a RIG-I translocon required for innate antiviral immunity.

Alcohol synergistically enhances the progression of liver disease and the risk for liver cancer caused by hepatitis C virus (HCV). However, the molecular mechanism of this synergy remains unclear. Here, we provide the first evidence that Toll-like receptor 4 (TLR4) is induced by hepatocyte-specific transgenic (Tg) expression of the HCV nonstructural protein NS5A, and this induction mediates synergistic liver damage and tumor formation by alcohol-induced endotoxemia. We also identify Nanog, the stem/progenitor cell marker, as a novel downstream gene up-regulated by TLR4 activation and the presence of CD133/Nanog-positive cells in liver tumors of alcohol-fed NS5A Tg mice. Transplantation of p53-deficient hepatic progenitor cells transduced with TLR4 results in liver tumor development in mice following repetitive LPS injection, but concomitant transduction of Nanog shorthairpin RNA abrogates this outcome. Taken together, our study demonstrates a TLR4-dependent mechanism of synergistic liver disease by HCV and alcohol and an obligatory role for Nanog, a TLR4 downstream gene, in HCV-induced liver oncogenesis enhanced by alcohol.

Background: Hepatitis C virus (HCV) induces autophagosomes in its host cells. Results: The HCV RNA replication complex colocalizes with autophagosomes, which are induced by HCV via a Class III PI3K-independent pathway. Conclusion: HCV induces autophagosomes and uses their membranes for its RNA replication. Significance: The perturbation of the autophagic pathway by HCV may have important consequences in HCV pathogenesis.

The antiviral innate immunity is the first line of host defense against virus infections. In mammalian cells, viral infections initiate the expression of interferons (IFNs) in the host that in turn activate an antiviral defense program to restrict viral replications by induction of IFN stimulated genes (ISGs), which are largely regulated by the IFN-regulatory factor (IRF) family and signal transducer and activator of transcription (STAT) family transcription factors. The mechanisms of action of IRFs and STATs involve several post-translational modifications, complex formation, and nuclear translocation of these transcription factors. However, many viruses, including human immunodeficiency virus (HIV), Zika virus (ZIKV), and herpes simplex virus (HSV), have evolved strategies to evade host defense, including alteration in IRF and STAT post-translational modifications, disturbing the formation and nuclear translocation of the transcription complexes as well as proteolysis/degradation of IRFs and STATs. In this review, we discuss and summarize the molecular mechanisms by which how viral components may target IRFs and STATs to antagonize the establishment of antiviral host defense. The underlying host-viral interactions determine the outcome of viral infection. Gaining mechanistic insight into these processes will be crucial in understanding how viral replication can be more effectively controlled and in developing approaches to improve virus infection outcomes.