Abstract
Simple SummaryEpstein-Barr Virus (EBV) infection is associated with various lymphomas and carcinomas as well as other diseases in humans. The transmembrane protein LMP1 plays versatile roles in EBV life cycle and pathogenesis, by perturbing, reprograming, and regulating a large range of host cellular mechanisms and functions, which have been increasingly disclosed but not fully understood so far. We summarize recent research progress on LMP1 signaling, including the novel components LIMD1, p62, and LUBAC in LMP1 signalosome and LMP1 novel functions, such as its induction of p62-mediated selective autophagy, regulation of metabolism, induction of extracellular vehicles, and activation of NRF2-mediated antioxidative defense. A comprehensive understanding of LMP1 signal transduction and functions may allow us to leverage these LMP1-regulated cellular mechanisms for clinical purposes. The Epstein–Barr Virus (EBV) principal oncoprotein Latent Membrane Protein 1 (LMP1) is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily with constitutive activity. LMP1 shares many features with Pathogen Recognition Receptors (PRRs), including the use of TRAFs, adaptors, and kinase cascades, for signal transduction leading to the activation of NFκB, AP1, and Akt, as well as a subset of IRFs and likely the master antioxidative transcription factor NRF2, which we have gradually added to the list. In recent years, we have discovered the Linear UBiquitin Assembly Complex (LUBAC), the adaptor protein LIMD1, and the ubiquitin sensor and signaling hub p62, as novel components of LMP1 signalosome. Functionally, LMP1 is a pleiotropic factor that reprograms, balances, and perturbs a large spectrum of cellular mechanisms, including the ubiquitin machinery, metabolism, epigenetics, DNA damage response, extracellular vehicles, immune defenses, and telomere elongation, to promote oncogenic transformation, cell proliferation and survival, anchorage-independent cell growth, angiogenesis, and metastasis and invasion, as well as the development of the tumor microenvironment. We have recently shown that LMP1 induces p62-mediated selective autophagy in EBV latency, at least by contributing to the induction of p62 expression, and Reactive Oxygen Species (ROS) production. We have also been collecting evidence supporting the hypothesis that LMP1 activates the Keap1-NRF2 pathway, which serves as the key antioxidative defense mechanism. Last but not least, our preliminary data shows that LMP1 is associated with the deregulation of cGAS-STING DNA sensing pathway in EBV latency. A comprehensive understanding of the LMP1 signaling landscape is essential for identifying potential targets for the development of novel strategies towards targeted therapeutic applications.
Highlights
Human herpesviruses are of particular importance in medical research in that they are associated with severe diseases including cancers in immunocompromised populations [1,2]
Further analyses have demonstrated that IRF4 and NFκB, both oncogenic transcription factors activated by Epstein–Barr Virus (EBV) Latent Membrane Protein 1 (LMP1) and Human T-cell Leukemia Virus-1 (HTLV1) Tax signaling pathways, transcriptionally upregulate LIMD1 expression in EBV- or HTLV1-transformed cells [76]
We have further shown that IRF5, the dominant-negative mutant of which is induced by TLR7 signaling in EBV latency, interacts with IRF7 and inhibits its activity stimulated by LMP1 [169]
Summary
Human herpesviruses are of particular importance in medical research in that they are associated with severe diseases including cancers in immunocompromised populations [1,2]. Epstein–Barr Virus (EBV), known as human herpesvirus 4 (HHV4), serves as a fascinating paradigm for the study of herpesvirus infection, replication, latency, and associated diseases, as well as host–pathogen interactions due to its ability to establish lifelong persistent infection in normal immunocompetent healthy hosts [3]. As the first identified human cancer virus, EBV infection is associated with various lymphomas and carcinomas, which most often occur in immunocompromised patients [7]. More than 50% of AIDS-related lymphomas (ARLs), which are a leading cause of HIV/AIDS-related cancer deaths even in the era of combined antiretroviral therapy [13], are associated with EBV infection [14,15]. The EBV Latent membrane protein 1 (LMP1) is a pleiotropic factor, which is constitutively active without the need of ligand stimulation and plays diverse roles through the whole EBV life cycle, including lytic, reactivation, and latency. We summarize recent research progress on LMP1 signaling, focusing on the novel components of LMP1 signalosome, including LIMD1, p62, and LUBAC, and the novel functions of LMP1 signaling, including induction of p62-mediated selective autophagy, regulation of metabolism, induction of extracellular vehicles, and activation of Keap1-NRF2-mediated antioxidative defense
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