Our lab utilizes molecular, biochemical, structural, cell biological and genetic approaches to reveal novel molecular mechanisms underlying virus pathogenesis and host innate immunity. Our research has focused on initial immune responses against RNA viruses including type I IFNs and proinflammatory cytokines. Our recent research reported that RIG-I-dependent antiviral signaling took place on an intracellular micro domain at the mitochondria-associated membrane (MAM). During acute viral infection, signaling components including RIG-I, MAVS, and others form stable singalsomes on the MAM and induce IFN production.

 

Intracellular innate immunity and mechanism of action of IFN against viruses

 

Viral infection of hepatocytes triggers intracellular antiviral innate immune responses through the recognition of pathogen associated molecular pattern (PAMPs) by pattern recognition receptors (PRRs) such as retinoic acid inducible gene I (RIG-I) which is a cytoplasmic HCV sensor molecule in the hepatocytes. Recognition of HCV triggers RIG-I interaction with the central adaptor protein, mitochondrial antiviral signaling (MAVS) protein, leading to the activation of the transcription factor interferon regulatory factor 3 (IRF3) and the production of type I interferon (IFN). Many of these same antiviral genes are also induced by IFN through the IFN receptor mediated Janus Kinase (Jak)- Signal Transducer and Activator of Transcription (STAT) signaling cascade. Thus, the hepatocyte has two distinct antiviral gene induction pathways: 1) RIG-I signaling upon HCV PAMP recognition (IFN induction pathway) or 2) by response to exogenous IFN (IFN response pathway). We are interested in how these pathways are regulated differently in the hepatocytes to cause the establishment of persistent hepatitis virus infections.

 

Post-translational Modifications of the RIG-I-like Receptors and their interacting proteins

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We have previously reported the formation of a mitochondrial targeting RIG-I “translocon”. This complex shuttles RIG-I to the mitochondria-associated membrane (MAM) to interact with the central adaptor protein, mitochondrial antiviral signaling (MAVS) protein, which is the master regulator of IFN induction. The post-translational modifications (PTM) of proteins, such as poly-ubiquitination and phosphorylation, have to shown to regulate RIG-I activation upon viral infections. Recently, we reported that deacetylation of RIG-I by HDAC6 is critical for RIG-I activation. We are interested in other types of PTMs in controlling the activities of RIG-I and RIG-I-like receptors.