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While most NOD‐like receptors (NLRs) are predominately expressed by innate immune cells, NLRC3, an inhibitory NLR of immune signaling, exhibits the highest expression in lymphocytes. The role of NLRC3 or any NLRs in B lymphocytes is completely unknown. Gammaherpesviruses, including human Epstein–Barr virus (EBV) and murine gammaherpesvirus 68 (MHV‐68), establish latent infection in B lymphocytes, which requires elevated NF‐κB. This study shows that during latent EBV infection of human B cells, viral‐encoded latent membrane protein 1 (LMP1) decreases NLRC3 transcript. LMP1‐induced‐NF‐κB activation suppresses the promoter activity of NLRC3 via p65 binding to the promoter. Conversely, NLRC3 inhibits NF‐κB activation by promoting the degradation of LMP1 in a proteasome‐dependent manner. In vivo, MHV‐68 infection reduces Nlrc3 transcripts in splenocytes, and Nlrc3‐deficient mice show greater viral latency than controls. These results reveal a bidirectional regulatory circuit in B lymphocytes, where viral latent protein LMP1 reduces NLRC3 expression, while NLRC3 disrupts gammaherpesvirus latency, which is an important step for tumorigenesis. [ABSTRACT FROM AUTHOR]

Retinoic acid-inducible gene I ( RIG-I) is a cytosolic pattern-recognition receptor that recognizes viruses and triggers anti-viral immune responses. Activation of intracellular RIG-I signalling is mediated through interferon- β ( IFN- β) promoter stimulator-1 ( IPS-1), an adaptor of RIG-I, which induces IFN regulatory factor ( IRF) 3 activation and type I IFN expression. The phosphatidylinositol-3-kinase ( PI3K) and Akt pathway is activated in host immune cells upon viral infection. However, the mechanism as to how they work in RIG-I signalling has not been fully elucidated. Therefore, we investigated the role of PI3K and Akt in the regulation of RIG-I-mediated IRF3 activation and type I IFN expression in macrophages. Our results show that Sendai virus infection, which is recognized by RIG-I, led to IRF3 activation and IFN- β expression and these responses were attenuated by the PI3K inhibitor ( LY294002) and an Akt dominant-negative mutant in the macrophage cell line( RAW264.7). IRF3 phosphorylation and dimerization as well as IFN- β expression induced by a synthetic RIG-I agonist, short poly(I:C), were suppressed by LY294002 or si RNA-Akt in bone marrow-derived macrophages. Suppression of PI3K and Akt using a dominant-negative mutant and si RNA knockdown resulted in attenuation of IRF3 activation and IFN- β expression induced by RIG-I itself or its adaptor, IPS-1. Association of Akt with IPS-1 increased with short poly(I:C) stimulation and required the pleckstrin homology domain of Akt and caspase-recruitment domain in IPS-1. Collectively, our results show that PI3K and Akt are required downstream of IPS-1 for RIG-I-mediated anti-viral immune responses. The results describe a novel, interactive relationship between RIG-I downstream signalling molecules resulting in efficient anti-viral immunity. [ABSTRACT FROM AUTHOR]