scholarly journals Epstein-Barr Virus-Encoded Latent Membrane Protein 2A Downregulates GCNT3 via the TGF-β1/Smad-mTORC1 Signaling Axis

2021 ◽  
Author(s):  
Juanjuan Liu ◽  
Yan Zhang ◽  
Caixia Yu ◽  
Jun Li ◽  
Wen Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Mtorc1 Signaling ◽  
Epstein Barr ◽  
Tgf Β1 ◽  
Novel Therapeutic

Increasing evidence shows that Epstein-Barr virus (EBV) infection is closely related to various lymphoid and epithelioid malignancies. However, the underlying mechanisms are unclear. GCNT3 (core 2β-1,6-acetylglucosaminyltransferase) is a new type of core mucin synthase, and its expression in EBV-associated gastric cancer (EBVaGC) is lower than that in EBV-negative gastric cancer (EBVnGC). EBV-encoded latent membrane protein 2A (LMP2A) is a transmembrane protein with tumorigenic transformation properties. Here, we demonstrated that LMP2A inhibited the transcription of GCNT3 by inhibiting Smad2/3 and Smad4. LMP2A restrained the activation of the mTORC1 pathway by inactivating the TGF-β1/Smad pathway and then downregulated GCNT3 expression. The mTORC1-GCNT3 pathway promoted cell proliferation and migration and inhibited G0/G1 cell arrest. Related proteins involved in epithelial-mesenchymal transition (EMT) were downstream molecules of the TGF-β1/Smad-mTORC1-GCNT3 pathway. GCNT3 inhibited autophagy by inducing mTORC1 phosphorylation. These findings indicate that targeting the TGF-β1/Smad-mTORC1-GCNT3 axis may represent a novel therapeutic target in GC. Importance Epstein-Barr virus (EBV) is an opportunistic pathogen, and the latent membrane protein 2A (LMP2A) encoded by EBV plays a key role in ensuring the incubation period of EBV. Glycosylation modification is an important marker of cancer cells, and recent studies have reported that it is related to EBV. Our conclusions provide deeper theoretical support for the role of LMP2A and TGF/Smad-mTORC1-GCNT3 in EBVaGC and help to understand glycosylation abnormalities in cancer. Our results may provide novel therapeutic targets for the treatment of gastric cancer against the TGF/Smad-mTORC1-GCNT3 signaling cascade.

scholarly journals Epstein-Barr virus in Burkitt’s lymphoma: A role for latent membrane protein 2A

Cell Cycle ◽  
2010 ◽  
Vol 9 (5) ◽  
pp. 901-908 ◽  
Author(s):  
Kathryn T. Bieging ◽  
Michelle Swanson-Mungerson ◽  
Alexandra C. Amick ◽  
Richard Longnecker
Keyword(s):  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Latent Membrane Protein ◽  
Burkitt's Lymphoma ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Immunohistochemical Detection of the Epstein-Barr Virus–Encoded Latent Membrane Protein 2A in Hodgkin's Disease and Infectious Mononucleosis

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1664-1672 ◽  
Author(s):  
G. Niedobitek ◽  
E. Kremmer ◽  
H. Herbst ◽  
L. Whitehead ◽  
C.W. Dawson ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Protein Expression ◽  
Infectious Mononucleosis ◽  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Latent Membrane Protein ◽  
Immunohistochemical Detection ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Epstein Barr

We describe two new monoclonal antibodies specific for the Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) that are suitable for the immunohistochemical analysis of routinely processed paraffin sections. These antibodies were applied to the immunohistochemical detection of LMP2A in Hodgkin's disease (HD). LMP2A-specific membrane staining was seen in the Hodgkin and Reed-Sternberg (HRS) cells of 22 of 42 (52%) EBV-positive HD cases, but not in 39 EBV-negative HD cases. In lymphoid tissues from patients with acute infectious mononucleosis (IM), interfollicular immunoblasts were shown to express LMP2A. This is the first demonstration of LMP2A protein expression at the single-cell level in EBV-associated lymphoproliferations in vivo. The detection of LMP2A protein expression in HD and IM is of importance in view of the proposed role of this protein for maintaining latent EBV infection and its possible contribution for EBV-associated transformation. Because LMP2A provides target epitopes for EBV-specific cytotoxic T cells, the expression of this protein in HRS cells has implications for the immunotherapeutic approaches to the treatment of HD.

scholarly journals Roles of the ITAM and PY Motifs of Epstein-Barr Virus Latent Membrane Protein 2A in the Inhibition of Epithelial Cell Differentiation and Activation of β-Catenin Signaling

2005 ◽  
Vol 79 (4) ◽  
pp. 2375-2382 ◽  
Author(s):  
Jennifer A. Morrison ◽  
Nancy Raab-Traub
Keyword(s):  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Nuclear Translocation ◽  
Cell Receptor ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Cellular Processes ◽  
Epstein Barr ◽  
Virus Latent Membrane Protein

ABSTRACT Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) is important for maintenance of latency in infected B lymphocytes. Through its immunoreceptor tyrosine-based activation motif (ITAM) and PY motifs, LMP2A is able to block B-cell receptor (BCR) signaling, bind BCR-associated kinases, and manipulate the turnover of itself and these kinases via a PY-mediated interaction with the Nedd4 family of ubiquitin ligases. In epithelial cells, LMP2A has been shown to activate the phosphatidylinositol 3′-OH kinase/Akt and β-catenin signaling pathways. In the present study, the biological consequences of LMP2A expression in the normal human foreskin keratinocyte (HFK) cell line were investigated and the importance of the ITAM and PY motifs for LMP2A signaling effects in HFK cells was ascertained. The ITAM was essential for the activation of Akt by LMP2A in HFK cells, while both the ITAM and PY motifs contributed to LMP2A-mediated accumulation and nuclear translocation of the oncoprotein β-catenin. LMP2A inhibited induction of differentiation in an assay conducted with semisolid methylcellulose medium, and the PY motifs were critical for this inhibition. LMP2A is expressed in the EBV-associated epithelial malignancies nasopharyngeal carcinoma and gastric carcinoma, and these data indicate that LMP2A affects cellular processes that likely contribute to carcinogenesis.

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