| Summary: | 碩士 === 國立陽明大學 === 微生物及免疫學研究所 === 100 === Retinoic acid gene I (RIG-I), a member of RIG-I-like receptors (RLRs), has emerged as a key factor in the recognition of viral RNA and the production of type I interferon (IFN) and proinflammatory cytokines that limit viral replication. To induce IFN-mediated innate response, RIG-I interacts with its downstream mitochondrial antiviral-signaling protein (MAVS) through its N-terminal caspase activation and recruitment domains (CARDs), and thereby recruit TRAF3 and TRAF6, which activate IFN-regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB), respectively. However, the regulation of RLR-signaling is largely unknown. Here we identified a proto-oncogene PIM1, a serine/threonine kinase, which might participate in RLR-signaling regulation. We found that overexpression of PIM1 strongly reduced IFN-β promoter activity induced by Sendai virus (SeV) or RIG-I, and a kinase dead PIM1 (PIM1 K67M) is unable to down-regulate the signal. We also examined the effects of PIM1on the phosphorylation of endogenous IRF3 and the expression of IRF3 downstream gene (interferon-β (IFN-β), interferon gamma-induced protein 10 kDa (IP-10) and interferon stimulating gene 56 (ISG56)), and the data demonstrated that PIM1 might play a negative role in RIG-I-mediated signaling pathway. On the other hand, PIM1 knockdown enhanced the SeV-induced IRF3 phosphorylation, as well as the mRNA expression of the downstream genes. The data from our previous study have suggested that PIM1 regulates the RLR signaling pathway probably at a step upstream of MAVS. Here we showed that PIM1 could interact with RIG-I at both the N terminal and the C terminal, but not the helicase, domains. Moreover, PIM1 kinase can phosphorylate RIG-I in vitro. These data collectively indicate that PIM1 may down-regulate RIG-I-mediated antiviral responses by phosphorylating RIG-I.
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