Abstract
BackgroundThe Innate immune system constitutes the first line of defense against pathogen infections. The Retinoic acid-inducible gene I (RIG-I) receptor recognizes triphosphorylated ssRNAs and dsRNA to initiate downstream signaling of interferon response. However, unregulated activity of these receptors could lead to autoimmune diseases. We seek to identify small molecules that can specifically regulate RIG-I signaling.Methodology/Principal FindingsEpigallocatechin gallate (EGCG), a polyphenolic catechin present in green tea, was identified in a small molecule screen. It was found to bind RIG-I and inhibits its signaling at low micromolar concentrations in HEK293T cells. Furthermore, EGCG dose-dependently inhibited the ATPase activity of recombinant RIG-I but did not compete with RIG-I interaction with RNA or with ATP. EGCG did not inhibit signaling by Toll-like receptors 3, 4, 9 or constitutive signaling by the adapter protein IPS-1. Structure activity relationship analysis showed that EGCG, its epimer GCG and a digallate-containing compound, theaflavin 3,3′ digallate (TFDG) were potent RIG-I inhibitors. EGCG also inhibited IL6 secretion and IFN- β mRNA synthesis in BEAS-2B cells, which harbors intact endogenous RIG-I signaling pathway.Conclusions/SignificanceEGCG and its derivatives could have potential therapeutic use as a modulator of RIG-I mediated immune responses.
Highlights
Multiple, at least partially overlapping, pathways are used to detect viral infections [1]
In our attempt to identify small molecule modulators of Retinoic acidinducible gene I (RIG-I) we identified a green tea polyphenol, Epigallocatechin gallate (EGCG), which could bind RIG-I and inhibit its activation of signal transduction
EGCG did not interfere with RNA or ATP binding by RIG-I and can affect the complex of RIG-I and RNA (Figure 2, 3 and 6)
Summary
At least partially overlapping, pathways are used to detect viral infections [1]. During RNA virus infection, doublestranded RNAs (dsRNA) and uncapped transcripts generated during replication can serve as pathogen-associated molecular patterns recognized by innate immune receptors [1,2]. Agonist binding by these receptors results in changes in signal transduction that can lead to establishment of antiviral responses as well as mediate adaptive immune responses. The exposed CARDs can interact with and activate its adaptor protein IPS-1 ( known as MAVS, VISA and Cardif), a mitochondrial membrane protein, to activate signal transduction through the transcription factors IRF3 and NF-kB resulting in increases in cytokine production [4,5]. We seek to identify small molecules that can regulate RIG-I signaling
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