A phosphomimetic-based mechanism of dengue virus to antagonize innate immunity

Chan YK, Gack MU. Nat Immunol. 2016 May; 17(5): 523-530.

Speaker: Yu-San Kao（高于珊）                                        Time: 14:00~15:00, Jun. 14, 2017

Commentator: Dr. Chia-Yi Yu（余佳益 老師）         Place: Room 601

Abstract：

Innate immunity and type I IFN responses function as the first line of defense against viral infections. Most viruses target these important elements to avoid being sensed or recognized in infected cells and to efficiently establish infection in the host. Previous study observed that dengue virus (DV) inhibits the production of type I interferon in primary human dendritic cells.¹ However, how DV escapes innate immunological detection by retinoic acid inducible gene-I (RIG-I) is unknown. RIG-I is a key cytosolic pathogen recognition receptor that initiates innate immune responses against many RNA viruses. Upon RIG-I binding of viral RNA triggers a conformational change and redistribution from the cytosol to mitochondria membrane where it binds the adaptor protein, MAVS. The mitochondria-targeting chaperone 14-3-3ε has been identified as a crucial mediator of the redistribution of RIG-I from the cytosol to mitochondrion-associated MAVS that acts by forming a ‘translocon’ complex with RIG-I and TRIM25.² In this study, the authors showed that the NS3 protein of DV bound to 14-3-3ε and prevented translocation of RIG-I to MAVS and thereby blocked antiviral signaling. They initially found the interaction of DV NS3 with 14-3-3ε and confirmed DV NS2B-NS3 did not cleave 14-3-3ε, TRIM25 or RIG-I. In agreement with that, NS3 alone, which has no proteolytic activity, can block the RIG-I and 14-3-3ε-mediated signaling. They further determined that DV NS3 bound to 14-3-3ε through the use of a highly conserved phosphomimetic RxEP motif. This study also demonstrated that mutant DV deficient in binding to 14-3-3ε and antagonism of RIG-I showed impairment of specific viral interferon-antagonistic mechanism and efficient activation of innate and adaptive immunity resulting in attenuation of viral growth. Their work reveals a novel phosphomimetic-based mechanism and provides a rational design of live attenuated vaccines against DV.

References：

1.  Rodriguez-Madoz JR, et al. Dengue virus inhibits the production of type I interferon in primary human dendritic cells. J Virol. 2010; 84(9): 4845-4850.

2.  Helene Minyi Liu, et al. The mitochondrial targeting chaperone 14-3-3ε regulates a RIG-I translocon that mediates membrane-association and innate antiviral immunity. Cell Host Microbe. 2012; 11(5): 528–537.