Virus-Infection or 5′ppp-RNA Activates Antiviral Signal through Redistribution of IPS-1 Mediated by MFN1

Abstract

In virus-infected cells, RIG-I-like receptor (RLR) recognizes cytoplasmic viral RNA and triggers innate immune responses including production of type I and III interferon (IFN) and the subsequent expression of IFN-inducible genes. Interferon-β promoter stimulator 1 (IPS-1, also known as MAVS, VISA and Cardif) is a downstream molecule of RLR and is expressed on the outer membrane of mitochondria. While it is known that the location of IPS-1 is essential to its function, its underlying mechanism is unknown. Our aim in this study was to delineate the function of mitochondria so as to identify more precisely its role in innate immunity. In doing so we discovered that viral infection as well as transfection with 5′ppp-RNA resulted in the redistribution of IPS-1 to form speckle-like aggregates in cells. We further found that Mitofusin 1 (MFN1), a key regulator of mitochondrial fusion and a protein associated with IPS-1 on the outer membrane of mitochondria, positively regulates RLR-mediated innate antiviral responses. Conversely, specific knockdown of MFN1 abrogates both the virus-induced redistribution of IPS-1 and IFN production. Our study suggests that mitochondria participate in the segregation of IPS-1 through their fusion processes.

Author Summary

Virus-infections, such as influenza and chronic hepatitis C, are prominent diseases and outbreaks of newly emerging viruses are serious problems for modern society. Higher animals, including humans, are genetically equipped with mechanisms, collectively known as innate immunity, to counteract viral infections. RIG-I-like receptor (RLR), a cytoplasmic sensor, contributes to immune regulation by detecting infections by RNA viruses and triggering a series of responses which results in the activation of innate antiviral genes. Furthermore, it has been demonstrated that IPS-1, the adaptor protein of RLR, is expressed on mitochondrial outer membrane. Mitochondrion is an organelle of prokaryotic cell origin; it regulates energy production, and is involved in cell growth and cell death. Why IPS-1 is located on the mitochondrial outer membrane and how mitochondria are involved in antiviral signaling are yet to be explained clearly. In this report, we discovered that mitochondrial fusion protein MFN1 plays a novel function to mediate IPS-1 redistribution, which appears to be a critical step in RLR signaling.