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LMP1 signaling pathway activates IRF4 in latent EBV infection and a positive circuit between PI3K and Src is required

Oncogene volume 36, pages 2265–2274 (2017)Cite this article

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Abstract

Interferon (IFN) regulatory factors (IRFs) have crucial roles in immune regulation and oncogenesis. We have recently shown that IRF4 is activated through c-Src-mediated tyrosine phosphorylation in virus-transformed cells. However, the intracellular signaling pathway triggering Src activation of IRF4 remains unknown. In this study, we provide evidence that Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) promotes IRF4 phosphorylation and markedly stimulates IRF4 transcriptional activity, and that Src mediates LMP1 activation of IRF4. As to more precise mechanism, we show that LMP1 physically interacts with c-Src, and the phosphatidylinositol 3 kinase (PI3K) subunit P85 mediates their interaction. Depletion of P85 by P85-specific short hairpin RNAs disrupts their interaction and diminishes IRF4 phosphorylation in EBV-transformed cells. Furthermore, we show that Src is upstream of PI3K for activation of both IRF4 and Akt. In turn, inhibition of PI3K kinase activity by the PI3K-speicfic inhibitor LY294002 impairs Src activity. Our results show that LMP1 signaling is responsible for IRF4 activation, and further characterize the IRF4 regulatory network that is a promising therapeutic target for specific hematological malignancies.

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Acknowledgements

This work was supported by an NIH NIDDK grant to ZQY/JPM (R01DK093526), an NIH NIAID grant to ZQY/JPM (R01AI114748), the American Society of Hematology Scholar Award to SN, and in part by the NIH grant C06RR0306551. We thank Dr Bill Sugden for providing pSV2-LMP1 and its deletion mutant pSV2-LMP1Δ(12-20). This publication is the result of work supported with resources and the use of facilities at the James H Quillen Veterans Affairs Medical Center. The contents in this publication do not represent the views of the Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

  1. Division of Infectious Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA

    L Wang, J Ren, G Li, J P Moorman, Z Q Yao & S Ning

  2. Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA

    L Wang, J Ren, G Li, J P Moorman, Z Q Yao & S Ning

  3. Hepatitis (HCV/HIV) Program, James H Quillen VA Medical Center, Johnson City, TN, USA

    J P Moorman & Z Q Yao

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Wang, L., Ren, J., Li, G. et al. LMP1 signaling pathway activates IRF4 in latent EBV infection and a positive circuit between PI3K and Src is required. Oncogene 36, 2265–2274 (2017). https://doi.org/10.1038/onc.2016.380

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