miR-30a enhanced RIG-I-mediated type I interferon antiviral response by targeting USP14

TL;DR

The study shows that miR-30a boosts the body's antiviral response by targeting USP14, which helps fight viruses like VSV and SeV.

Contribution

The novel finding is that miR-30a enhances type I IFN signaling by inhibiting USP14, revealing a new miRNA–innate immunity regulatory axis.

Findings

miR-30a promotes IFN and ISG production to inhibit viral replication in macrophages.

miR-30a targets USP14 mRNA to enhance RIG-I ubiquitination and antiviral responses.

The miR-30a-USP14-RIG-I axis represents a new regulatory mechanism in innate immunity.

Abstract

Type I interferon (IFN) signaling plays a prominent role in the host innate immune defense against viral infection. The regulatory roles of miRNAs on the innate immune response remain to be further explored. Although miR-30a has been implicated in the regulation of various viral life cycles, the underlying mechanism on type I IFN signaling remains controversial. Herein, miR-30a was identified as a regulator of type 1 IFN production in macrophages. We observed that miR-30a expression was significantly decreased by vesicular stomatitis virus (VSV) or Sendai virus (SeV) infection in THP-1 cells. In return, overexpression of miR-30a promoted viral infection-triggered IFN and ISGs production to inhibit VSV or SeV replication. Mechanistically, miR-30a inhibited USP14 expression by binding with the 3′UTR of mRNA. USP14 was identified as an inhibitor of IFN signaling by removing the K63-linked ubiquitination from RIG-I, as previously reported. Consequently, miR-30a, by downregulating USP14 expression, enhanced the K63-linked ubiquitination of RIG-I to exert broad-spectrum antiviral effects. Overall, this study revealed a novel antiviral mechanism of miR-30a through the miR-30a-USP14-RIG-I axis and enriched miRNA–innate immunity regulatory networks.

miRNAs are involved in the regulation of innate immune responses and affect the life cycle of viruses. In this study, we identified miR-30a as a potent positive regulator of type I IFN signaling. The further mechanistic study revealed that miR-30a, by targeting and inhibiting USP14 expression, promoted RIG-I K63 ubiquitination to enhance type I IFN responses, thereby resulting in broad-spectrum antiviral effects against multiple viruses. As a complex regulatory network, the activation of type I interferon responses could subsequently reduce miR-30a expression to prevent the dysregulated activation. The insights gained could be crucial for developing innovative antiviral strategies to combat viral infections.

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