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

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.