Ribosome Protein L4 is essential for Epstein–Barr Virus Nuclear Antigen 1 function

Shen, Chih-Lung; Liu, Cheng-Der; You, Ren-In; Ching, Yung-Hao; Liang, Jun; Ke, Liangru; Chen, Yalin; Chen, Hong-Chi; Hsu, Hao-Jen; Liou, Je-Wen; Kieff, Elliott; Peng, Chih‐Wen

doi:10.1073/pnas.1525444113

Cited by 23 publications

(17 citation statements)

References 44 publications

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“… 13 EBNA1 is an EBV-encoded nuclear antigen which plays a critical role in EBV genome maintenance, replication and postmitotic segregation and is the only EBV protein expressed in all types of EBV-infected cells. 4 We have previously demonstrated that EBV-EBNA1 promotes the production of Treg cells in a TGFβ1-dependent manner. 14 However, the role and specific mechanism of EBV-EBNA1 in chemoattraction of Treg cells remains poorly understood.…”

Section: Discussionmentioning

confidence: 97%

EBV-EBNA1 constructs an immunosuppressive microenvironment for nasopharyngeal carcinoma by promoting the chemoattraction of Treg cells

Huo

Luo

Deng

et al. 2020

J Immunother Cancer

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BackgroundNasopharyngeal carcinoma (NPC) is primarily caused by the Epstein-Barr virus (EBV) infection in NPC endemic areas. EBNA1 is an EBV-encoded nuclear antigen, which plays a critical role in the maintenance and replication of EBV genome. However, the mechanisms of EBNA1-promoted NPC immune escape are unknown. Regulatory T (Treg) cells are among the key regulators in restraining antitumor responses. However, the mechanisms of accumulation of Treg cells in NPC have not been defined. This study attempted to identify the detailed mechanisms of EBNA1 functions as a tumor accelerator to promote NPC immune escape by enhancing chemoattraction of Treg cells.MethodsmRNA profiles were determined by next-generation sequencing in NPC cells. In vitro and in vivo assays were performed to analyze the role of EBNA1 in regulation of recruitment of Treg cells. Colocation and coimmunoprecipitation analyzes were used to identify the SMAD3/c-JUN complex. Chromatin immunoprecipitation assay and dual luciferase reporter assays were designed to demonstrate c-JUN binding to miR-200a promoter and miR-200a targeting to CXCL12 3’Untranslated Regions. The hepatocellular carcinoma models were designed to demonstrate universality of the CXCL12-CXCR4-Treg axis in promoting immune evasion of various tumors.ResultA novel molecular mechanism was identified that involves EBV-EBNA1-stimulated chemotactic migration of Treg cells toward NPC microenvironment by upregulation of the transforming growth factor-β1 (TGFβ1)-SMAD3-PI3K-AKT-c-JUN-CXCL12-CXCR4 axis and downregulation of miR-200a. EBV-EBNA1 promotes the chemoattraction of Treg cells by governing the protein–protein interactions of the SMAD3/c-JUN complex in a TGFβ1-dependent manner in vitro and in vivo. TGFβ1 suppresses miR-200a by enhancing the SMAD3/c-JUN complex. miR-200a negatively regulates the CXCL12 chemokine by direct targeting of the CXCL12 3’UTR region. However, CXCL12 acts as the target gene of miR-200a and as an inhibitor of miR-200a transcription, and inhibition of miR-200a by CXCL12 is mediated by c-JUN, which directly binds to the miR-200a promoter and forms a c-JUN-miR-200a-CXCL12-c-JUN feedback loop. In addition, enhanced CXCL12 efficiently attracts CXCR4-positive Treg cells to remodel an immunosuppressive microenvironment.ConclusionsEBV-EBNA1 promotes chemotactic migration of Treg cells via the TGFβ1-SMAD3-PI3K-AKT-c-JUN-miR-200a-CXCL12-CXCR4 axis in the NPC microenvironment. These results suggest that EBV-EBNA1 may serve as a potential therapeutic target to reshape the NPC microenvironment.

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Section: Discussionmentioning

confidence: 97%

EBV-EBNA1 constructs an immunosuppressive microenvironment for nasopharyngeal carcinoma by promoting the chemoattraction of Treg cells

Huo

Luo

Deng

et al. 2020

J Immunother Cancer

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“…Moreover, many RPs exhibit dramatically higher levels of expression in cells where virus propagate rapidly, such as RPL4 in EBV-infected cells [94] and RPS27a in Hepatitis B virus-infected cells [137]. These RPs with high expression can be considered as targets of antiviral drug carriers for specific tissue/cell drug delivery.…”

Section: Applications and Prospectivementioning

confidence: 99%

Regulation of Ribosomal Proteins on Viral Infection

2019

Cells

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Ribosomal proteins (RPs), in conjunction with rRNA, are major components of ribosomes involved in the cellular process of protein biosynthesis, known as “translation”. The viruses, as the small infectious pathogens with limited genomes, must recruit a variety of host factors to survive and propagate, including RPs. At present, more and more information is available on the functional relationship between RPs and virus infection. This review focuses on advancements in my own understanding of critical roles of RPs in the life cycle of viruses. Various RPs interact with viral mRNA and proteins to participate in viral protein biosynthesis and regulate the replication and infection of virus in host cells. Most interactions are essential for viral translation and replication, which promote viral infection and accumulation, whereas the minority represents the defense signaling of host cells by activating immune pathway against virus. RPs provide a new platform for antiviral therapy development, however, at present, antiviral therapeutics with RPs involving in virus infection as targets is limited, and exploring antiviral strategy based on RPs will be the guides for further study.

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“…The ChIP assay was performed to detect the binding of EBNA1-oriP according to previous reports (Shen et al, 2016). The Immunoprecipitation Kit (Millipore) was used for the assay.…”

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

“…EBNA1-oriP binding has been validated to be necessary for the replication initiation of EBV genome (Shen et al, 2016). Here, we investigated the effect of CYPA knockdown on the oriP luciferase activity in cells transfected with an oriP luciferase reporter in C2089 cells.…”

Section: Cypa Regulates Transcription Initiation Of the Ebv Genome VImentioning

confidence: 99%

Epstein-Barr Virus Nuclear Antigen 1 Recruits Cyclophilin A to Facilitate the Replication of Viral DNA Genome

Xin

Liu

et al. 2019

Front. Microbiol.

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Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)-mediated DNA episomal genome replication and persistence are essential for the viral pathogenesis. Cyclophilin A (CYPA) is upregulated in EBV-associated nasopharyngeal carcinoma (NPC) with unknown roles. In the present approach, cytosolic CYPA was found to be bound with EBNA1 into the nucleus. The amino acid 376-459 of the EBNA1 domain was important for the binding. CYPA depletion attenuated and ectopic CYPA expression improved EBNA1 expression in EBV-positive cells. The loss of viral copy number was also accelerated by CYPA consumption in daughter cells during culture passages. Mechanistically, CYPA mediated the connection of EBNA1 with oriP (origin of EBV DNA replication) and subsequent oriP transcription, which is a key step for the initiation of EBV genome replication. Moreover, CYPA overexpression markedly antagonized the connection of EBNA1 to Ubiquitinspecific protease 7 (USP7), which is a strong host barrier with a role of inhibiting EBV genome replication. The PPIase activity of CYPA was required for the promotion of oriP transcription and antagonism with USP7. The results revealed a strategy that EBV recruited a host factor to counteract the host defense, thus facilitating its own latent genome replication. This study provides a new insight into EBV pathogenesis and potential virus-targeted therapeutics in EBV-associated NPC, in which CYPA is upregulated at all stages.

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Ribosome Protein L4 is essential for Epstein–Barr Virus Nuclear Antigen 1 function

Cited by 23 publications

References 44 publications

EBV-EBNA1 constructs an immunosuppressive microenvironment for nasopharyngeal carcinoma by promoting the chemoattraction of Treg cells

EBV-EBNA1 constructs an immunosuppressive microenvironment for nasopharyngeal carcinoma by promoting the chemoattraction of Treg cells

Regulation of Ribosomal Proteins on Viral Infection

Epstein-Barr Virus Nuclear Antigen 1 Recruits Cyclophilin A to Facilitate the Replication of Viral DNA Genome

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