MicroRNA-27a Regulates Host Antiviral Innate Immune Responses And The Underlying Mechanisms

When infected by virus, the immune cells recognize viral components through pattern recognition receptors and activate transduction of downstream signaling pathways, thereby initiate antiviral innate immune response by inducing the expression of type Ⅰ interferons and proinflammatory cytokines. Type Ⅰ Interferon (IFN) plays critical roles in host antiviral response and is regulated by multiple mechanisms. Whether and how viruses evade these mechanisms for their own survival is of great interest. Accordingly, pre-screened by high-through miRNA chip, we found a significant downregulation of the miR-27a expression in mouse peritoneal macrophages after infected by RNA virus VSV. Further studies showed that the expression of miR-27a is dependent on time and dose of VSV stimulation, and its expression is regulated by IFN/JAK/STAT1 signaling pathway and is dependent on RUNX1 protein. Downregulation of miR-27a expression will significantly inhibit the expression of type Ⅰ IFN induced by virus and consequently promote viral replication. Mechanistically, through the gene expression profiling analysis by microarray, we found that miR-27a can target to sialic acid lectin receptors Siglecl and TRIM family E3 ubiquitin ligase TRIM27, over-expression of miR-27a can reduce the expression of Siglec1 and TRIM27 at both the mRNA and protein level. Furthermore, we found that Siglec1 can interact with DAP 12, which then associates with and activated tyrosine phosphatase SHP2. Then the activated SHP2 recruits the ubiquitin E3 ligase TRIM27 to target on TBK1. TRIM27 induces K48-linked ubiquitination of TBKl at Lys251 and Lys372 and promotes TBKl degradation via the proteasome pathway, ultimatly resulting in negative regulation of the expression of type I interferon. We further constructed a miR-27a-sponge transgenic mouse, and further validated the functions of miR-27a in vivo. After intraperitoneal injection of VSV, compared with the control group, we found that the IFN-β expression was significantly decreased in the serum of miR-27a-sponge mice. HE staining indicated that more severe infiltration of polymorphonuclear cells and interstitial pneumonitis were found in the lungs of miR-27a-sponge mice, and more VSV titer in the liver, spleen and lung was observed. Thus, we have demonstrated that down-regulation of miR-27a expression inducd by the viral infection can enhance the expression of negative regulators Siglecl and TRIM27, then promotes TBKl degradation, thereby feedback inhibiting the expression of type Ⅰ interferons and enhancing the viral replication. These results suggest that virus uses miR-27a to escape host antiviral innate immune response. Therefore, we suggest a new mechanism for viral evasion of host antiviral response.