The Epstein–Barr Virus Latent Membrane Protein 1 (LMP1) Enhances TNF Alpha-Induced Apoptosis of Intestine 407 Epithelial Cells: The Role of LMP1 C-Terminal Activation Regions 1 and 2

Abstract

Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) can protect some kinds of lymphocytes from apoptotic cell death. In contrast, the present study showed that the expression of LMP1 induced high susceptibility to tumor necrosis factor alpha (TNFα)-induced apoptosis in intestine 407 epithelial cells, without affecting expression of TNF receptors I and II. LMP1-deletion mutants lacking either C-terminal activation region (CTAR)-1 or CTAR-2 had ability to enhance TNFα-induced apoptosis, whereas the deletion of both activation regions completely abolished the induction of high susceptibility to TNFα. Phosphorylation of the NFkB-inhibitory molecule IkB-α, another biological activity of TNFα, was not enhanced by LMP1-expression. LMP1 upregulated antiapoptotic gene A20 expression, suggesting that A20 can not block TNFα-induced apoptosis in this cell system. Apoptosis triggered by TNFα in LMP1-expressing intestine 407 cells was blocked by inhibitors of caspases-8 and -3. It is therefore concluded that in intestine 407 epithelial cells, LMP1 enhances primarily signal cascade responsible for TNFα-induced apoptosis, which occurs at a level upstream of acting site of caspases-8 and -3 and that CTAR-1 and CTAR-2 are involved in enhancement of TNFα-induced apoptosis.