Long Noncoding RNA ITPRIP-1 Positively Regulates the Innate Immune Response through Promotion of Oligomerization and Activation of MDA5

Abstract

Emerging evidence indicates that long noncoding RNAs (lncRNAs) regulate various biological processes, especially innate and adaptive immunity. However, the relationship between lncRNAs and the interferon (IFN) pathway remains largely unknown. Here, we report that lncRNA ITPRIP-1 (lncITPRIP-1) is involved in viral infection and plays a crucial role in the virus-triggered IFN signaling pathway through the targeting of melanoma differentiation-associated gene 5 (MDA5). LncITPRIP-1 can be induced by viral infection, which is not entirely dependent on the IFN signal. Besides, there is no coding potential found in the lncITPRIP-1 transcript. LncITPRIP-1 binds to the C terminus of MDA5, and it possesses the ability to boost the oligomerization of both the full length and the 2 caspase activation and recruitment domains of MDA5 in a K63-linked polyubiquitination-independent manner. Amazingly, we also found that MDA5 can suppress hepatitis C virus (HCV) replication independently of IFN signaling through its C-terminal-deficient domain bound to viral RNA, in which lncITPRIP-1 plays a role as an assistant. In addition, the expression of lncITPRIP-1 is highly consistent with MDA5 expression, indicating that lncITPRIP-1 may function as a cofactor of MDA5. All the data suggest that lncITPRIP-1 enhances the innate immune response to viral infection through the promotion of oligomerization and activation of MDA5. Our study discovers the first lncRNA ITPRIP-1 involved in MDA5 activation. Hepatitis C virus infection is a global health issue, and there is still no available vaccine, which makes it urgent to reveal the underlying mechanisms of HCV and host factors. Although RIG-I has been recognized as the leading cytoplasmic sensor against HCV for a long time, recent findings that MDA5 regulates the IFN response to HCV have emerged. Our work validates the significant role of MDA5 in IFN signaling and HCV infection and proposes the first lncRNA inhibiting HCV replication by promoting the activation of MDA5 and mediating the association between MDA5 and HCV RNA, the study of which may shed light on the MDA5 function and treatment for hepatitis C patients. Our suggested model of how lncITPRIP-1 orchestrates signal transduction for IFN production illustrates the essential role of lncRNAs in virus elimination.

RIG-I-like receptors: their regulation and roles in RNA sensing

“…Through the iCLIP assay, the authors showed that Lnczc3h7a not only interacts with TRIM25 but also, through a short RNA stem-loop structure, with the helicase domain of RIG-I, suggesting that Lnczc3h7a acts as a molecular scaffold to enhance RIG-I-TRIM25 complex formation; this promoted TRIM25-mediated K63-linked ubiquitylation of RIG-I and, ultimately, its ability to form signalling-active oligomers early during infection. With regard to MDA5 activation, lnc-ITPRIP-1 was shown to interact with the sensor, stabilizing its binding to viral RNAs and promoting its oligomeric signalling-competent form 157 . Finally, besides the described lncRNAs and miRNAs that directly regulate RLR activities, others act downstream of RLRs or broadly regulate inflammatory gene or ISG expression [158][159][160] .…”

Systematic discovery of endogenous human ribonucleoprotein complexes

“…11! regulate the oligomerization state of proteins both positively (Bleichert and Baserga, 2010;Huthoff et al, 2009;Xie et al, 2018) and negatively (Yoshida et al, 2004). Our data suggests that while the majority of RNA-associated proteins form higher-order assemblies with RNA, the oligomerization of 21% is potentially inhibited by RNA.…”

LncRNAs in HCV Infection and HCV-Related Liver Disease

“…RIG-I and the canonical sensor TLR3 (toll-like receptor 3) can also be activated by the viral dsRNA (double-stranded RNA) produced during replication [18,19]. In addition, it has been recently shown that the canonical sensor MDA5 (melanoma differentiation-associated protein 5) can also bind viral RNA and activate IFN [20]. Activated sensors can bind MAVS (mitochondrial antiviral signaling protein) and TRIF (Toll-Interleukin Receptor-domain-containing adapter-inducing interferon-β), which trigger the induction of transcription factors NF-κB (nuclear factor κb) and IRF (interferon regulatory factors), in charge of activating IFN synthesis.…”