Emerging Roles of lncRNAs Regulating RNA-Mediated Type-I Interferon Signaling Pathway

Abstract

The type-I interferon (IFN-I) signaling pathway plays pivot roles in defending against pathogen invasion. Exogenous ssRNA and dsRNA could be immunogenic. RNA-mediated IFN signaling is extensively studied in the field. The incorrect functioning of this pathway leads to either autoimmune diseases or suffering from microorganism invasion. From the discrimination of "self" and "non-self" molecules by receptors to the fine-tune modulations in downstream cascades, all steps are under the surveillance featured by complex feedbacks and regulators. Studies in recent years highlighted the emerging roles of long noncoding RNAs (lncRNAs) as a reservoir for signaling regulation. LncRNAs bind to targets through the structure and sequence, and thus the mechanisms of action can be complex and specific. Here, we summarized lncRNAs modulating the RNA-activated IFN-I signaling pathway according to the event order during the signaling. We hope this review help understand how lncRNAs are participating in the regulation of IFN-I signaling.

Keywords: ISG; PAMP; PRR; lncRNA; type-I interferon.

Figure 1

RNA-mediated IFN-I signaling pathway. Pathogen invasion introduces RNA into the endosome or dsRNAs in the cytoplasm. Receptors recognize the RNA molecules and trigger the activation of downstream cascades through their adaptors. IFN-I expression is induced and secreted to activate the ISG expression through IFN-I receptors. Five-sided star represents phosphorylation modification.

Figure 2

Brief summary of lncRNAs regulating IFN signaling. Based on proteins and events order, lncRNAs affecting RLRs, TLRs, TBK1, IRF3, JAK-STAT axis, IFN, and ISG expression are discussed. +, positive regulation. -, negative regulation.

Figure 3

LncRNAs regulates RLR-mediated IFN signaling. LncRNA NEAT1, lnczc3h7a, AVAN, and lncITPRIP-1 positively regulate IFN signaling through targeting proteins indicated in the figure. Lnc-Lsm3b, lncATV, and lncRHOXF1 negatively regulate IFN signaling by targeting RIG-I and RLRs. Five-sided star represents phosphorylation modification. LncRNA in blue represents negative regulators; lncRNA in red is positive regulators for IFN signaling.

Figure 4

LncRNAs regulate TLR-mediated IFN signaling. LncRNA ALVE1-AS1 enhances TLR3-mediated IFN signaling. LncRNA-155 targets PTP1B. LncRNA-PART1 negatively affects TLR-mediated IFN signaling. “U” represents ubiquitination modification. Five-sided star represents phosphorylation modification. LncRNA in blue represents negative regulators; lncRNA in red is positive regulators for IFN signaling.

Figure 5

LncRNAs regulate downstream cascades for IFN-I activation. LncRNA-GM targets GSTM1 to disrupt GSTM1-directed S-glutathionylation of TBK1 (SSG), thus promoting TBK1 for its kinase activity. LncRNA MaIL1 targets OPTN to facilitate OPTN-TBK1 binding for TBk1 kinase activity. LncRNA OASL-IT1, lncRNA-ISIR, and lncLrrc55-AS facilitate IRF3 phosphorylation. LncRNA Malat1 downregulates IRF3 abundance by targeting TDP43. LncRNA-MxA inhibits IRF3 binding onto the IFN promoter region. Five-sided star represents phosphorylation modification. LncRNA in blue represents negative regulators; lncRNA in red is positive regulators for IFN signaling.

Figure 6

LncRNAs regulates IFN and ISG transcription. IFN signals through binding to the receptors and activation of downstream JAK-STAT cascades. LncRNA RP11-2B6.2, linc00513, and lnc13 enhance JAK-STAT activities. LncRNA IVRPIE, IRF1-AS, and lncRNA#32 enhance IFN and ISG transcription. Lnc641, PVT1, lncRNA625, and LUCAT1 downregulate JAK-STAT activity. LncRNA TSPOAP1-AS1, NRAV, and lncRNA-CMPK2 decrease IFN and ISG transcription. Five-sided star represents phosphorylation modification. LncRNA in blue represents negative regulators; lncRNA in red is positive regulators for IFN signaling.

Figure 7

A summary of lncRNAs discussed in this review. From IFN signaling activation to ISG transcription, discussed lncRNAs are positioned at sites of action. Five-sided star represents phosphorylation modification. LncRNA in blue represents negative regulators; lncRNA in red is positive regulators for IFN signaling.