Primate-specific miR-576-3p sets host defense signalling threshold

Abstract

MicroRNAs (miRNAs) have been shown to regulate viral infection, but the miRNAs that target intracellular sensors and adaptors of innate immunity have not been fully uncovered. Here we conduct a miRNA mimic screen and validation with miRNA inhibitors in cells infected with vesicular stomatitis virus (VSV) to identify miRNAs that regulate viral-host interactions. We identify miR-576-3p as a robust regulator of infection by VSV and other RNA and DNA viruses. While a miR-576-3p mimic sensitizes cells to viral replication, inhibition of endogenous miR-576-3p prevents infection. miR-576-3p is induced by IRF3 concomitantly with interferon and targets STING, MAVS and TRAF3, which are critical factors for interferon expression. Interestingly, miR-576-3p and its binding sites are primate-specific and miR-576-3p levels are reduced in inflammatory diseases. These findings indicate that induction of miR-576-3p by IRF3 triggers a feedback mechanism to reduce interferon expression and set an antiviral response threshold to likely avoid excessive inflammation.

Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis

“…Accordingly, treatment of these cells with histone deacetylase or histone-lysine methyltransferases inhibitors partially rescued cGAS mRNA expression in CA cells examined (LS174T, SW1417, SW48) (Figure S5C). It may also be apparent that alternate mechanisms of cGAS suppression exist, such as those involving miRNAs (Yarbrough et al, 2014). To determine if reconstitution of cGAS expression rescued STING-dependent dsDNA signaling, we examined control hTERT or SW480, HT116 (cGAS rescued by 5AZADC) or LS174T (cGAS not rescued by 5AZADC) CA cells.…”

MicroRNA-30c Modulates Type I IFN Responses To Facilitate Porcine Reproductive and Respiratory Syndrome Virus Infection by Targeting JAK1

“…It is not surprising that viruses can take advantage of host miRNAs that act as suppressors of IFN-I production to generate a suitable environment for their replication. Such miRNAs include the well-characterized miR-146a (18)(19)(20), miR-21 (21), and miR-576-3p (22). The crucial antiviral effects of IFN-I are dependent on the activation of the JAK-STAT pathway (7).…”

Self-DNA, STING-dependent signaling and the origins of autoinflammatory disease

“…New insight has been gained into the nature of the self-DNA responsible for pro-inflammatory cytokine production including those 'activators' triggering STING. The importance of preventing self-DNA from accumulating in the cytosol is becoming readily evident, as well as our understanding of how the cell strides to achieve this [16,46]. In addition, it is clear that the cell has gone to significant lengths to ensure that STING is not 'switched on' for long periods.…”