Rhabdovirus-Inducible MicroRNA-210 Modulates Antiviral Innate Immune Response via Targeting STING/MITA in Fish

We report here the identification and characterization of a protein, ERIS, an endoplasmic reticulum (ER) IFN stimulator, which is a strong type I IFN stimulator and plays a pivotal role in response to both non-self-cytosolic RNA and dsDNA. ERIS (also known as STING or MITA) resided exclusively on ER membrane. The ER retention/retrieval sequence RIR was found to be critical to retain the protein on ER membrane and to maintain its integrity. ERIS was dimerized on innate immune challenges. Coumermycin-induced ERIS dimerization led to strong and fast IFN induction, suggesting that dimerization of ERIS was critical for self-activation and subsequent downstream signaling.

The innate immune system detects pathogen- and host-derived double-stranded DNA exposed to the cytosol and induces type I interferon (IFN) and other cytokines. Here, we identified interferon-inducible tripartite-motif (TRIM) 56 as a regulator of double-stranded DNA-mediated type I interferon induction. TRIM56 overexpression enhanced IFN-β promoter activation after double-stranded DNA stimulation whereas TRIM56 knockdown abrogated it. TRIM56 interacted with STING and targeted it for lysine 63-linked ubiquitination. This modification induced STING dimerization, which was a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent induction of IFN-β. Taken together, these results indicate that TRIM56 is an interferon-inducible E3 ubiquitin ligase that modulates STING to confer double-stranded DNA-mediated innate immune responses. Copyright © 2010 Elsevier Inc. All rights reserved.

The type I interferon (IFN) alpha and beta promoters have been a leading paradigm of virus-activated transcriptional regulation for more than two decades, and have contributed substantially to our understanding of virus-inducible gene regulation, the coordinated activities of NF-kappaB and IRF transcription factors, the temporal and spatial recruitment of co-activators to the enhanceosome, and signaling pathways that trigger the innate antiviral response. In 2003, the ISICR Milstein Award was presented to John Hiscott of McGill University and Tom Maniatis of Harvard University for their ongoing research describing the mechanisms of regulation of type 1 interferon genes and specifically for the identification of key signaling kinases involved in phosphorylation of the transcription factors IRF-3 and IRF-7. The specific roles played by IRFs and the IKK-related kinases TBK1 and IKKvarepsilon are now recognized within the broader framework of TLR and RIG-I signaling pathways. This review summarizes the unique features of the IKK-related kinases and offers a summary of recent advances in the regulation of the early host response to virus infection.