Abstract
Mitochondrial antiviral signaling protein (MAVS) is an essential adaptor molecule that is responsible for antiviral signaling triggered by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), leading to the induction of type I interferon in innate immunity. Previous studies have shown that certain viruses evade the innate immune response by cleaving the MAVS protein. However, little is known about how MAVS is regulated in response to foreign RNA, including both single-stranded (ss) and double-stranded (ds) RNA, because most previous reports have shown that the cleavage of MAVS is executed by proteases that are induced or activated by the invading RNA viruses. Here, we report that MAVS mRNA is degraded in response to polyinosinic-polycytidylic acid (polyI:C), a synthetic dsRNA, in A549 cells. RNA interference (RNAi) experiments revealed that both ssRNA- and dsRNA-associated pattern-recognition receptors (PRRs) were not involved in the degradation of MAVS mRNA. Foreign RNA also induced the transient degradation of the MAVS protein. In the resting state, the MAVS protein was protected from degradation by interferon regulatory factor 3 (IRF3); moreover, the dimerization of IRF3 appeared to be correlated with the rescue of protein degradation in response to polyI:C. The overexpression of MAVS enhanced interferon-β (IFN-β) expression in response to polyI:C, suggesting that the degradation of MAVS contributes to the suppression of the hyper-immune reaction in late-phase antiviral signaling. Taken together, these results suggest that the comprehensive regulation of MAVS in response to foreign RNA may be essential to antiviral host defenses.
Highlights
The antiviral defense system consists of innate and adaptive immunity
We initially found that the introduction of polycytidylic acid (polyI):C, a synthetic viral doublestranded RNA analog, significantly down-regulated the expression of mitochondrial antiviral signaling protein (MAVS) mRNA in A549 cells
new castle disease virus (NDV) infection significantly down-regulated the level of MAVS mRNA (Fig. 3B) These results suggested that the effect of viral infection on MAVS mRNA down-regulation differs among RNA viruses
Summary
The antiviral defense system consists of innate and adaptive immunity. The innate immune system is the initial reaction of mammalian cells against invading pathogens. The recognition of pathogen-associated molecular patterns (PAMPs) on the surface of the pathogens by pattern recognition receptors (PRRs) is the key to the activation of the inherent innate immune response [1]. Among the PRRs, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including RIG-I [2], melanoma differentiation-associated gene-5 (MDA-5) [3] and laboratory of genetics and physiology 2 (LGP2) [4], are expressed in various types of cells. The exposed CARDs interact with a downstream adaptor molecule, mitochondrial antiviral signaling protein (MAVS) [6], which is known as virus-induced signaling adaptor (VISA) [7], interferon (IFN)-b promoter stimulator-1 (IPS-1) [8] and caspase activation and recruitment domain adaptor inducing IFN-b (Cardif) [9]. The coordinated activation of IRF3 and NF-kB eventually induces the secretion of type I IFNs and pro-inflammatory cytokines that have antiviral activities [11]
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