Abstract
Mitochondrial antiviral signaling protein (MAVS), an adaptor protein, is activated by RIG-I, which is critical for an effective innate immune response to infection by various RNA viruses. Viral infection causes the RIG-I-like receptor (RLR) to recognize pathogen-derived dsRNA and then becomes activated to promote prion-like aggregation and activation of MAVS. Subsequently, through the recruitment of TRAF proteins, MAVS activates two signaling pathways mediated by TBK1-IRF3 and IKK- NF-κb, respectively, and turns on type I interferon and proinflammatory cytokines. This study discovered that NEDD4 binding protein 3 (N4BP3) is a positive regulator of the RLR signaling pathway by targeting MAVS. Overexpression of N4BP3 promoted virus-induced activation of the interferon-β (IFN-β) promoter and interferon-stimulated response element (ISRE). Further experiments showed that knockdown or knockout N4BP3 impaired RIG-I-like receptor (RLR)-mediated innate immune response, induction of downstream antiviral genes, and cellular antiviral responses. We also detected that N4BP3 could accelerate the interaction between MAVS and TRAF2. Related experiments revealed that N4BP3 could facilitate the ubiquitination modification of MAVS. These findings suggest that N4BP3 is a critical component of the RIG-I-like receptor (RLR)-mediated innate immune response by targeting MAVS, which also provided insight into the mechanisms of innate antiviral responses.
Highlights
As the first barrier system of the body, innate immunity plays a vital role in removing foreign pathogens and guiding the body to produce effective adaptive immune responses
To further confirm whether NEDD4 binding protein 3 (N4BP3) interacted with Mitochondrial antiviral signaling protein (MAVS), the Flag-N4BP3 expression plasmid was co-transfected with empty vector, HA-labeled RIG-I, MAVS, and TBK1 plasmids, respectively, in 293T human kidney cells
By conducting a dual-luciferase reporter and ELISA assay in 293T cells, we found that N4BP3 could potentiate Sendai virus (SeV)-induced activation of IFN-β promoter and interferon-stimulated response element (ISRE) in a dose-dependent manner (Figures 1B,C)
Summary
As the first barrier system of the body, innate immunity plays a vital role in removing foreign pathogens and guiding the body to produce effective adaptive immune responses. Pathogen-associated molecular patterns (PAMPs) are initially recognized, which induces downstream effector genes, including type I interferons (IFNs) and proinflammatory cytokines (Akira et al, 2006). When MAVS form prion protein aggregates, they can recruit E3 ubiquitin ligase and downstream effector proteins TNF receptor-associated factors 2 (TRAF 2), TRAF 3, and TRAF 6 to become an active “signaling body” (Liu et al, 2013). As a member of the Fezzi family, the NEDD4 binding protein (N4BP3) has been reported to modulate axon and dendrite branches It is expressed in the neural tissues of early Xenopus embryos, including the eyes, brain, and neural crest cells (Kiem et al, 2017). Knockdown or knockout of N4BP3 can inhibit RLR-mediated activation of IRF3, induction of downstream antiviral genes, and cellular antiviral responses. Our findings reveal a previously unknown function of N4BP3 and provide insight into the mechanisms of innate antiviral responses
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