The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis

Abstract

Long noncoding RNA (LncRNA), a noncoding RNA over 200nt in length, can regulate glycolysis through metabolic pathways, glucose metabolizing enzymes, and epigenetic reprogramming. Upon viral infection, increased aerobic glycolysis providzes material and energy for viral replication. Mitochondrial antiviral signaling protein (MAVS) is the only protein-specified downstream of retinoic acid-inducible gene I (RIG-I) that bridges the gap between antiviral immunity and glycolysis. MAVS binding to RIG-I inhibits MAVS binding to Hexokinase (HK2), thereby impairing glycolysis, while excess lactate production inhibits MAVS and the downstream antiviral immune response, facilitating viral replication. LncRNAs can also regulate antiviral innate immunity by interacting with RIG-I and downstream signaling pathways and by regulating the expression of interferons and interferon-stimulated genes (ISGs). Altogether, we summarize the relationship between glycolysis, antiviral immunity, and lncRNAs and propose that lncRNAs interact with glycolysis and antiviral pathways, providing a new perspective for the future treatment against virus infection, including SARS-CoV-2.

Interferon Signaling-Dependent Contribution of Glycolysis to Rubella Virus Infection

“…Figure 5 sets the results on the IFNAR/IFNLR1 KO A549 cells in the context of the interaction between IFN generation and IFN signaling and glycolysis. As described by Ren and colleagues, glycolysis and the antiviral IFN pathway are connected, which includes the association of mitochondrial antiviral-signaling protein (MAVS) with hexokinase II (HKII) as the key glycolytic enzyme catalyzing the reaction of glucose (Glc) to glucose-6-phosphate (G6P) [ 17 ]. As summarized in the review by Ren et al, MAVS localizes to the outer membrane of mitochondria and serves as an adaptor downstream of the dsRNA recognition receptor RIG-I (retinoic acid inducible gene I) and is thus required for the generation of IFNs.…”

LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation

“…Recently, an increasing number of studies have proven that lncRNAs, which are transcripts with a length of more than 200 nucleotides and without the coding protein ability, expressed by a viral host can regulate multiple immunological and metabolic pathways upon infection by acting as guides, decoys, or scaffolds ( Ren et al, 2021 ; Sajjad et al, 2021 ; Yang Q. et al, 2021 ). Type I IFN and its downstream signaling pathway components are modulated in two ways by host lncRNAs.…”

The lncRNAs involved in regulating the RIG-I signaling pathway

“…In addition to regulating multiple pathways involved in the antiviral innate immune response at various regulatory points, lncRNAs also regulate the glycolytic network ( Liu et al., 2022 ). LncRNAs have been reported to cluster during the glycolytic cycle and inhibit viral replication through the disruption of hexokinase (HK2), voltage-dependent anion channel (VDAC), and MAVS ternary complex, thereby inhibiting glycolysis during viral infection ( Ren et al., 2021 ). MAVS, the protein that is specific to signaling downstream of RIG-I, is reported to be the connecting link between antiviral immunity and glycolysis ( Zhang et al., 2019 ).…”

“…The lncRNA taurine upregulated 1 (TUG1) ( Lin et al., 2018 ), plasmacytoma variant translocation 1 (PVT1) ( Chen et al., 2019 ), and deleted in lymphocytic leukaemia 2 (DLEU2) ( Dong et al., 2021 ) have been reported to positively regulate the expression of HK through their ceRNAs. While lncRNAs may regulate the HK-dependent lactate production by upstream kinase stimulation, MAVS is inhibited by HK and lactate ( Ren et al., 2021 ). This exploration of the relationship among lncRNAs, HK, and RIG-I provides several insights.…”