215: Alternative splicing variants of stimulator of interferon genes present a differential ability to induce interferon beta

Abstract

The innate immune system provides a primary line of defense against pathogens in eukaryotes. This defense system is based on the detection of pathogens followed by the activation of a coordinated response culminating in the suppression of infection. Chordates present a complex detection of pathogen associated molecular patterns (PAMPs) that leads to the activation of interferon (IFN). Stimulator of interferon genes (STING) is a critical protein involved in IFN-β induction in response to infection by some DNA and RNA pathogens, including herpes simplex virus-1 (HSV-1), Listeria monocytogenes and vesicular stomatitis virus (VSV). We decided to obtain STING cDNA from HeLa cells from total STING mRNA. In addition to the already reported wild type (Wt) STING cDNA, we observed several other PCR products that were cloned and sequenced. In addition to Wt STING, we discovered additional products as a result of alternative STING mRNA splicing. We have tested the ability of the different STING over-expressed isoforms to induce IFN-β, interferon regulatory factor 3 (IRF-3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) specific pathways. Preliminary experiments reveal the inability of alternative spliced variants to induce IFN-β. Alternative spliced variants however, show a differential strength in inhibiting Wt STING mediated IFN-β induction. STING is an endoplasmic reticulum resident factor. Interestingly, the alternative spliced forms of STING have a different location pattern as compared to STING Wt. Overall, our data present appealing new aspects of STING biology regulation that will shed light on the control of STING in the cellular innate immune-biology. Future experiments should clarify the behavior of all STING isoforms which will help to understand the mechanisms involved in fighting against some pathogen derived human diseases.