The latent membrane protein 1 (LMP1) oncogene of Epstein-Barr virus can simultaneously induce and inhibit apoptosis in B cells.
The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) regulates its own expression and the expression of human genes via its two functional moieties; the transmembrane domains of LMP1 are required to regulate its expression via the unfolded protein response (UPR) and autophagy in B cells, and the carboxy-terminal domain of LMP1 activates cellular signaling pathways that affect cellular proliferation and survival. An apparent anomaly in the complex regulation of the UPR and autophagy by LMP1 is that the induction of either pathway can lead to cellular death, yet neither EBV-infected B cells nor B cells expressing only LMP1 die. Thus, we sought to understand how B cells that express LMP1 survive. The transmembrane domains of LMP1 activated apoptosis in B cells, the apoptosis required the UPR, and the carboxy-terminal domain of LMP1 blocked this apoptosis. The expression of the mRNA of Bcl2a1, encoding an antiapoptotic homolog of BCL2, correlated directly with the expression of LMP1 in EBV-positive B-cell strains, and its expression inhibited the apoptosis induced by the transmembrane domains of LMP1. These findings illustrate how the carboxy-terminal domain of LMP1 supports survival of B cells in the presence of the deleterious effects of the complex regulation of this viral oncogene.
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Zachary L
ZL
Pratt
Jingzhu
J
Zhang
Bill
B
Sugden
D017209:Apoptosis / Q000235:genetics*; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D016000:Cluster Analysis; D004847:Epithelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
C096816:BCL2-related protein A1; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D035683:MicroRNAs; D015778:Minor Histocompatibility Antigens; D009856:Oncogene Proteins, Viral; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014763:Viral Matrix Proteins