![]() ![]() The interaction between RIG-I and MAVS at MAM is critical for triggering IFNβ induction. We have previously identified that activated RIG-I will then redistribute to the mitochondrion-associated membrane (MAM) through interaction with mitochondrial chaperone protein 14-3-3ε via the CARDs of RIG-I. Once bound on the RNA with 5’-triphosphate (5’-ppp) or short dsRNA, a conformational change of RIG-I will occur, and the C-terminus repressor domain (RD) of RIG-I will release the CARDs for interactions with accessory proteins for redistribution and then interaction with downstream signaling molecules. The molecular mechanisms of RIG-I activation have been extensively studied in the past decade. The N-terminus caspase activation and recruitment domains (CARDs) function as the activation domain to directly interact with the CARD of downstream adaptor protein MAVS, of which interaction is critical for the activation of the type I interferon signaling pathway. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist.Īmong the RIG-I-like Receptor (RLR) family, RIG-I and MDA5 share a number of structural similarities, and both of them include three distinct domains. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: Supported by MOST (Ministry of Science and Technology, R.O.C, ) grant MOST 104-2320-B-002-057, MOST 105-2628-B-002-014-MY3 and by NHRI (National Health Research Institutes, ) grant NHRI-EX106-10417SC, NHRI-EX107-10417SC. Received: Accepted: JanuPublished: February 11, 2019Ĭopyright: © 2019 Lin et al. PLoS Pathog 15(2):Įditor: Mehul Suthar, Emory University, UNITED STATES Viral proteins which antagonize 14-3-3η to impair MDA5-dependent antiviral signaling may be suitable targets for antiviral therapy or be modified to generate potential vaccine strains.Ĭitation: Lin J-P, Fan Y-K, Liu HM (2019) The 14-3-3η chaperone protein promotes antiviral innate immunity via facilitating MDA5 oligomerization and intracellular redistribution. These findings reveal a novel component which participating in the control system of MDA5-dependent signaling pathway. The lack of 14-3-3η in host cells leads to the kinetically-delayed oligomerization of MDA5, which is a key steps of the activation of MDA5-mediated anti-viral signaling pathway. Our results suggested that the activation of MDA5 is promoted by the chaperone protein 14-3-3η. Besides, the establishment of well functional adaptive immune response to viruses is depending on the timely activation of innate immune antiviral signaling pathway. During viral infection RIG-I-like receptors (RLRs), including MDA5, play essential roles in initiating type I interferon signaling pathway and preventing virus infection or replication in host cells. In this study, we utilized biochemistry and molecular biology approaches to defines the molecular mechanisms by which melanoma differentiation-associated protein 5 (MDA5), a cytoplasmic RNA helicase and pattern recognition receptor molecule, is regulated by 14-3-3η to govern its innate immune signaling activity. In conclusion, our results uncover a novel function of 14-3-3η to promote the MDA5-dependent IFNβ induction pathway by reducing the immunostimulatory potential of viral dsRNA within MDA5 activation signaling pathway. We also demonstrated that 14-3-3η is essential in boosting the activation of MDA5-dependent antiviral innate immunity during viral infections. Consequently, the MDA5-dependent IFNβ promoter activities as well as IFNβ mRNA expression level were also decreased in the 14-3-3η knocked-down cells. Knock-down of 14-3-3η in Huh7 cells impaired and delayed the kinetics of MDA5 oligomerization, which is a critical step for MDA5 activation. We found that several 14-3-3 isoforms may interact with MDA5 through the CARDs (N-MDA5), but 14-3-3η was the only isoform that could enhance MDA5-dependent IFNβ promoter activities in a dose-dependent manner. Here we show that 14-3-3η is an essential accessory protein for MDA5-dependent type I IFN induction. However, the molecular mechanisms of MDA5 activation remain less understood. Upon RNA ligand stimulation, we observed the redistribution of MDA5 from the cytosol to mitochondrial membrane fractions. MDA5 belongs to the RIG-I-like receptor family and plays a non-redundant role in recognizing cytoplasmic viral RNA to induce the production of type I IFNs. ![]()
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